Category Archives: Epigenetics

Type 2 diabetes is characterised by elevated blood glucose levels. This can cause complications that lead to damage to the kidneys, nerves, and the retina in eyes. Other complications can lead to heart diseases and diabetic foot ulcers, which eventually require amputation.

Until fairly recently type 2 diabetes was considered a major health issue only in developed countries. But theres been an increase in prevalence in developing countries. This has been attributed to rapid urbanisation, increased fast food consumption and general lack of exercise.

The diabetes crisis is forecast to worsen. According to the International Diabetes Federation, African countries can expect an increase of up to 143% in the number of people with diabetes by 2045. Its latest report shows that South Africa has the highest prevalence of diabetes on the continent, and the highest number of diabetes-related deaths. The countrys diabetes-related expenditure 23% of the total health budget spent on the management of the disease in 2019 is also the highest.

The rise in diabetes cases needs to be curbed to ease the demand on healthcare systems. To achieve this, new and innovative ways of assessing the levels of risk people face from diabetes are needed. These must be specific to populations on the continent.

My colleagues and I are involved in research aimed at integrating genetic mechanisms and risk factors associated with diabetes and its associated complications, specifically in an African setting. In particular, we have done research on diabetes diagnosis. Our research aims to shed light on new avenues for assessing diabetes risk.

Conventional methods of diabetes diagnosis and management include the oral glucose tolerance test and the HbA1c test. But these have serious shortcomings.

The glucose tolerance test is cumbersome and time-consuming. It also requires a person to fast before having blood drawn. They are given a glucose solution and blood samples may then be drawn at different intervals. The aim is to measure how well, or poorly, their body is able to return their glucose levels back to normalcy.

There are also concerns about the overall accuracy of these tests.

For its part, studies have shown that the results of the HbA1c test may be compromised by factors such as age, ethnicity and anaemias.

All this points to the need for novel, and more sensitive approaches to diabetes diagnosis and therapy.

One area of research that appears to offer the promise of a solution is the booming field of epigenetics. This field of study looks at how our behaviours and surrounding environment may induce genetic changes that predispose us to certain diseases.

When it comes to diabetes, microRNAs (miRNAs) have been the talk of the town in the past decade. These molecules control which proteins are developed, and which proteins arent. Abnormal expression of these miRNAs may result in reduced amounts of proteins involved in essential bodily processes, or an overproduction of proteins which may have adverse effects. The underproduction of a miRNA involved in insulin production ultimately leads to reduced insulin levels and uncontrolled glucose levels in the blood.

Emerging evidence suggests that altered expressions of these miRNAs may either precede or play a role in the development of diseases such as type 2 diabetes.

The study of genetic mechanisms such as miRNAs is known as epigenetics. This is an umbrella of various mechanisms revolving around genetic changes that may occur due to our habits and surrounding environment. These adverse genetic changes may subsequently result in increased risk of disease.

Our surroundings and how we live govern our predisposition to developing certain lifestyle-oriented diseases, such as type 2 diabetes. Research focus must shift towards understanding the complex interplay between our genetic make-up and the environments we live in. Doing this will redefine therapies and management of lifestyle diseases and curb their growing prevalence. One such avenue is research in miRNAs.

In a recent study we identified miRNAs specifically two, 30a-5p and 182-5p which are associated with abnormal glucose levels. We screened three separate groups: a control group with normal glucose levels; a prediabetic group of people with intermediate glucose levels; and a group of people with newly diagnosed type 2 diabetes.

We observed higher levels of the miRNAs in the prediabetic and diabetic groups, in comparison to the normal group. There was more of an increase in the prediabetic group versus the normal group. This told us that for some reason, people with early-stage diabetes have higher levels of these miRNAs. This could indicate that this is either a compensatory response by the body to curb the disease progression, or a knock-on effect of disease progression.

Either way, our results showed that measuring the expression of these miRNAs could be used as a tool for potentially identifying people with prediabetes.

Our next question was: How well can miRNA expression analysis perform in identifying prediabetes and full-blown diabetes, in comparison to known and acknowledged tests?

To answer it, we statistically compared the use of the two miRNAs to that of the HbA1c test. The results showed that the miRNA 182-5p outperformed the HbA1c test in distinguishing prediabetes. This demonstrated that the miRNAs, in particular 182-5p, could be considered as potential novel biomarkers in identifying people at risk of developing diabetes early enough for interventions to be implemented.

In the light of advances in epigenetics research, doors are slowly beginning to open when it comes to personalised treatment regimens and disease management. Considering the influence our surrounding environment has on our health, scientists have begun exploring suggestions that treatment approaches specific to population groups in a particular region may be the future, particularly when it comes to lifestyle-oriented diseases.

Our findings are important because they underscore why personalised approaches and interventions offer potential solutions to designing innovative new breakthroughs in medicine. Identifying genetic trends that are specific to our population, such as these miRNAs, may improve overall diagnostics, therapy and management of type 2 diabetes.

This would, in turn, alleviate the pressure on healthcare systems.

Read more:
We're on the hunt for novel ways to assess the risk of type 2 diabetes - The Conversation CA

Introduction

Diabetic nephropathy, now commonly recognized as diabetic kidney disease (DKD), occurs in diabetic patients, especially those with poor long-term glycemic control,1 causing high morbidity and risk of death. As lifestyles and diets have changed in recent years, the global incidence of diabetes mellitus (DM) has increased annually, as reported by the International Diabetes Federation, which estimates that the incidence of diabetes mellitus (DM) will increase to 700 million in 2045.2 Consequently, diabetic kidney disease will increase social financial costs and threaten human health. DKD is defined by changes in the structure and function of the kidneys. The primary renal structural changes in DKD are mesangial matrix expansion, extracellular matrix accumulation, glomerular and tubular basement membrane thickening, and podocyte injury, eventually contributing to glomerulosclerosis and tubulointerstitial fibrosis.3,4 Clinically, microalbuminuria refers to the daily amount of urinary albumin between 30 mg-300 mg, also known as incipient nephropathy.5 Persistent microalbuminuria (>300mg/day) is called macroalbuminuria or overt nephropathy, followed by renal injury, ultimately leading to ESRD.35 The pathogenesis of DKD is multifactorial and involves many mechanisms such as oxidative stress, metabolic disturbance, activation of the renin-angiotensin-aldosterone system (RAAS), production of inflammatory factors, profibrotic transforming growth factor-1 (TGF-1), and genetic susceptibility, among which genetic predisposition explains some diabetic patients who do not properly control their glycemia but do not develop DKD.4,6 While some patients with diabetes still develop DKD even if they maintain good glycemic control,7 growing evidence demonstrates the relationship between epigenetic mechanisms and gene expression associated with diabetic complications,8 stressing the role of epigenetic modifications and metabolic memory in diabetic complications. Current diabetic kidney disease treatment strategies include blood pressure control, glycemic control, weight reduction, and intensive lifestyle interventions.9 The most effective drugs for DKD treatment are the combined use of RAAS blockers and Sodium-glucose cotransporter 2 (SGL2) inhibitors.10,11 However, the implementation of these measures seems not likely to improve longer-term outcomes, for example, the reversal and reduction of DKD progression in many patients. The increasing rates of DKD suggest a further understanding of underlying mechanisms to find better novel therapies for the clinical management of DKD.1214

Over the past decade, epigenetics has expanded rapidly in many fields and participates in the pathophysiology of DKD. Furthermore, environmental stimuli and inflammation are considered to mediate epigenetic mechanisms.15 Environmental factors, such as metabolites, contribute to the development of diabetes and DKD, which could regulate epigenetic status. That is to say, epigenetic modifications may play a critical role in DKD.12,16,17 In recent years, histone post-translational modifications (PTMs) have been reported to involve regulating DKD-related gene expression, such as connective tissue growth factor (CTGF), collagen-1[], and plasminogen activator inhibitor-1 (PAI-1).18,19 However, our knowledge of the magnitude of the relationship for histone modifications at individual gene sites with diabetic kidney disease and the underlying mechanisms is limited. In this review, we summarize current findings of histone modifications and DNA methylation in DKD, mainly highlighting the role of histone acetylation and methylation in DKD.

The term diabetic nephropathy was replaced by diabetic kidney disease (DKD) by the Kidney Disease Outcomes Quality Initiative (KDOQI), in line with the chronic kidney disease (CKD) classification.20 Traditionally, DKD is characterized by diffuse or nodular glomerulosclerosis. DKD has traditionally been recognized as a change in hemodynamics and metabolic disturbance. These changes can activate the expression of metabolic product, cytokines, chemokines, and immune system,21,22 as well as dysregulating signaling pathways, such as the oxidative stress2326 and profibrotic pathways.27,28 Furthermore, endothelial cell apoptosis exposed to sustained hyperglycemia could lead to kidney injury. These circulating renal factors have a cross-talk relationship to accelerate kidney damage and cause irreversible injury. DKD not only destroys the kidney itself but damages other organs, resulting in more serious diabetic comorbidities.

Microenvironmental changes and multidimensional pathology in DKD have updated conventional knowledge. Several different factors can enhance the pathogenic pathway initiated and maintained by hyperglycemia in the kidney. These include haemodynamic factors, including impaired autoregulation, hyperperfusion and hypoperfusion, as well as metabolic factors, including excess fatty acids, carbonyl and oxidative stress, and activation of the reninangiotensinaldosterone system (RAAS).29 These factors by themselves do not cause DKD but promote and enhance common pathogenic mechanisms in the presence of diabetes, including increased levels of growth factors, vasoactive hormones, cytokines and chemokines in the kidney. For example, vascular susceptibility to oxidative stress could be increased by endothelial dysfunction under high glucose condition, then endothelial dysfunction and subsequent microvascular rarefaction could also reduce blood flow, ultimately leading to hypoxia.4 The pathological manifestation of DKD is the accumulation of extracellular matrix in the glomeruli and tubules and the increased deposition of collagen, fibronectin, and laminin in the mesangial matrix, glomerular basement membrane, and tubulointerstitium.30

The conventional view is that the relationship between diabetes and mitochondrial dysfunction and complications are related to the harmful effects of hyperglycemia; however, further recognition of the stimulation of mitochondrial biogenesis and mitochondrial electron transport chain activity is more conducive to the treatment of DKD.23 Advanced technology in metabolomics, bioinformatics, and systems biology tools open a new window to find the mechanism of DKD. Similarly, considerable evidence shows that macrophage accumulation is a feature of kidney injury and it can produce pro-inflammatory factors, reactive oxygen species (ROS), and metalloproteinases, which lead to renal damage.31,32 Many studies have demonstrated that macrophages are closely associated with the decrease in the glomerular filtration rate (GFR) and histological changes.33,34 However, the mechanism of M2 macrophages how to promote renal repair and reduce the progression of DKD remains controversial, which is worthy of further study. Meanwhile, autophagy involved in the pathogenesis of diabetic kidney disease is also well described in the literature,35 which highlights the regulation of autophagy in diabetic kidney disease. Although long after attainment of glycemic control, the incidence of diabetic complications can still be induced by the exposure of target cells in memory to hyperglycemia.3638 The Diabetes Control and Complications Trial (DCCT) indicated that patients with type 1 diabetes in the intensive glycemic control group had a lower rate and severity of complications compared with those in the conventional group,39,40 in the follow-up observational Epidemiology of Diabetes Intervention and Complications (EDIC) study, patients in the initial intensive treatment group sustained to maintain a low risk of complications relative to those on conventional therapy.40 The continuous effects of high glucose on metabolic memory are a major obstacle to the effective management of diabetic complications. Substantial evidences support the role of epigenetic mechanisms in metabolic memory, recommending to target these mechanisms which may provide a new therapy to treat the diabetic complications.

Epigenetic modifications regulate gene expression, not the change in DNA sequences.41,42 They can occur in response to environmental stimuli, including diet, metabolic disorders, exercise, oxidative stress, inflammation, and drugs.41 These changes can be passed down to offspring, but can potentially be reversed. Epigenetic modifications include DNA methylation, histone modifications, and non-coding RNAs. At present, more than 100 kinds of modifications have been described, including methylation, acetylation, phosphorylation, sumoylation, ubiquitylation, citrullination, biotinylation, crotonylation, and ADP ribosylation.

In this report, we briefly introduce the epigenetic regulations that have been studied in kidney disease, especially DKD, and then introduce research and the latest developments in histone modification of acetylation and methylation involved in the pathogenesis of DKD. Non-coding RNA has been extensively reviewed and is beyond the scope of this study.43

DNA methylation, recognized as a silencing marker, involves the addition of a methyl group to the 5-position of cytosines and primarily occurs on 5-cytosines of CpG dinucleotides and to a lesser extent in non-CG contexts.44,45 The function of DNA methylation is highly dependent on the location of the CpG in the genome.46 In general, methylation of DNA at gene promoter areas can repress transcription and gene expression, whereas at gene bodies it can activate transcription and modulate alternative splicing.12

Histones are highly conserved, alkaline, positively charged proteins, that contain core histones (H2A, H2B, H3, and H4) and linker histones (H1 and H5).45,47 Similar structures in the four core histones are characterized by a conserved central motif domain and an unstructured amino-terminal tail. The unit structure components of chromatin, called the nucleosome, consists of DNA wrapped around an octamer of histone proteins, which contains an H3-H4 tetramer and two H2A-H2B dimers.48 The post-translational modification (PTM) of histones is the main mechanism to regulate chromatin structure, commonly occurring on the amino acid residues lysine, arginine, serine, tyrosine, and threonine and ultimately influencing transcriptional activity.49 The enzymes that mediate histone modification including acetyltransferases, methyltransferases are called epigenetic writers; deacetylases and demethylases are called epigenetic erasers; and proteins recognizing acetylated proteins at promoters and enhancers are called epigenetic readers (for example, bromodomain-containing protein 4).5052

Post-translational modifications (PTMs) of histone proteins include lysine acetylation (KAc), lysine methylation (Kme), arginine methylation, serine ubiquitylation, and threonine phosphorylation. To date, lysine (K), arginine (R) in both methylation and acetylation are the most widely researched, and phosphorylation, ubiquitination, and sumoylation have also been described.

Histone acetylation involves histone acetyltransferases (HATs) transferring an addition of an acetyl group to the lysine of core histones. Generally, histone acetylation is enriched at promoters and enhancers of actively transcribed genes but decreased in the suppressed genomic region. As acetyl can reduce the negative charge of DNA and make chromatin more easily accessible to transcription factors (TFs) and their coactivators,53 acetylation of lysine residual histones is usually associated with transcriptionally active genes. Three main HATs families include Gcn5-related N-acetyltransferases (GNATs: GCN5 and PCAF), MYST (MOZ and Ybf2/Sas3), Sas2, Tip60, and p300/CREB-binding protein (CBP). Conversely, histone deacetylation is catalyzed by histone deacetylases (HDACs), and histone deacetylation can regulate transcriptional repression by allowing chromatin compaction. Acetyl groups in lysine residues of histones and non-histone proteins can be removed by HDACs.54 Four classes of HDAC have been identified, Class I (HDACs 1, 2, 3, and 8), Class II (HDACs 4, 5, 6, 7, 9, and 10), Class III (SIRT1-7), and Class IV HDAC (HDAC11), which shares similar conserved residues with Classes I and II HDACs. Class I HDACs are expressed ubiquitously, mainly localizing in the nucleus, and demonstrate high enzymatic activity, whereas Class II HDACs show different expression patterns with tissue-specific roles and localize in the nucleus and cytoplasm.63 Classes, I, II, and IV are dependent on Zn2+, whereas Class III HDACs require NAD+ as a co-factor rather than Zn2+ for their enzymatic functions.55 HDAC inhibitors are ineffective against Class III (SIRT1-7). In general, H3K9ac, H3K14ac, H3K18ac, H3K23ac, and H3K27ac are enriched at promoters of transcriptional genes and contribute to gene expression. The association of histone acetylation in DKD progression has been verified in human renal tissues.5658 H3K9 acetylation (H3K9ac) levels were significantly increased in renal biopsies from patients with DKD.56 CHIP assays obtained from the glomeruli of diabetic mice compared with normal conditions in vivo exhibited increased induction of Pai1 (as pro-fibrotic genes) and p21 were related to the enrichment of H3K9ac and H3K14ac at the two gene transcriptional promoters.59 Overexpression of H3K9/14Ac levels was reported at the CTGF, PAI-1, and FN-1 promoters in kidneys of diabetic mice, which were associated with p300/CBP-mediated histone acetylation.60 The antidiabetic agent metformin, is widely used as a first-line treatment for patients with type 2 diabetes mellitus, and it has been reported metformin improves glucose metabolism by stimulating CBP phosphorylation, then triggers the dissociation of the CREB-CBP-TORC2 transcription complex, leading to reducing gluconeogenic enzyme gene expression.61 A recent study showed that STZ-induced diabetic mice kidney could reduce acetylation of nephrin, while reduction of nephrin acetylation may be alleviated by MicroRNA-29a, thus protecting against hyperglycemia-induced podocyte dysfunction.62 In another study, high glucose-induced hyperacetylation of the redox-regulating protein p66Shc promoter in podocytes with diabetic kidney disease increased protein p66Shc expression. Protease-activated protein C (aPC) reversed hyperacetylation of the p66Shc promoter and decreased mitochondrial ROS formation in podocytes.63 Taken together, these studies indicate an important role of histone acetylation in kidney diseases.

Histone methylation mainly occurs on the amino acid residues of lysine and arginine. Unlike histone acetylation, histone methylation functions as an information marker to store rather than change the charge of histones to disturb its contact with DNA.64 Histone methylation has three different forms, mono-, di-, or trimethyl, for lysine or arginine residues, which increases the complexity of PTMs. Therefore, either gene activation or repression in histone methylation is determined by the extent of methylation as well as different residues modified.65 Generally, H3K4me1/2/3, H3K36me2/3, and H3K79me1/2 are related to transcriptionally active gene regions, whereas H3K9me2/3, H4K20me3, and H3K27me3 are associated with repressive gene regions. H3K4me2 andH3K4me3 are fully enriched at transcriptional promoters, leading to gene expression. In contrast, H3K9me3 and H3K27me3 are enriched at inactive or slicing gene promoters, which could inhibit gene expression.65,66 Lysine methylation (Kme) is catalyzed by histone methyltransferases (HMTs). However, histone lysine demethylases remove methyl groups from histones, resulting in the demethylation of histones. The first histone demethylase was lysine methylase 1 (LSD1), which could specifically remove the methylation of H3K4 and H3K9.67,68 Many lysine demethylases were identified and renamed lysine demethylases (KDMs) due to their different specificity to various histone lysine residues and non-histone proteins.6971 Given the high selectivity of these enzymes to targeted histone residues, HMTs are classified as two types: arginine methyltransferases (PRMTs) and lysine methyltransferases (KMTs). Lysine methyltransferases (KMTs) include two families based on the catalytic sequence, one is the SET domain-containing KMTs (Su(var)39, enhancer of zeste and trithorax), and the other is a non-SET domain, for example, DOT1L. Histone methylation is dynamic, reversible modification that is regulated by HMTs and KDMs.17 Interestingly, HMTs and KDMs possess substrates specific for lysine residues. For example, methylation of H3K36 is specifically mediated by SET2, and the demethylation of trimethyl H3K36 andH3K9 is regulated by JHDM3/JMJD (trimethyl demethylases), whereas H3K36me2 and H3K36me1 are only demethylated by JHDM1A instead of JHDM3/JMJD. Similarly, methylation of H3K27 and H3K79 is mediated by EZH2 and DOT1, respectively.64 Histone methylation has been considered one of the most stable PTMs and considerable evidence has demonstrated that histone methylation plays a key role in contributing to the pathogenesis of DKD in preclinical in vivo and in vitro models. Because HMTs are involved in histone methylation, some of the targeted HMTs, small-molecule modulators, have been used to test the therapeutic effects in experimental kidney disease. Interestingly, in type 1 diabetic rat kidney, a decreased level of H3K9me2 on the Col1a1 gene promoter was observed, accompanied by decreased expression of SUV39H1 (a histone methylase, specifically catalyzed H3K9me2/3), which is involved in the development of diabetic renal fibrosis. In diabetic conditions, decreased expression of SUV39H1 HMTs was also demonstrated by Villeneuve et al72 and Chen et al.73 Additionally, decreased histone H3K9me3 levels at the promoters of some pro-inflammatory or pro-fibrotic genes also contributed to the development of DKD.58,74,75 Lin et al found HG decreased histone H3K9me3 levels at the promoters of the fibronectin and p21WAF1 genes in mesangial cells while accelerating HG-induced cell hypertrophy, which was attenuated by Suv39h1 overexpression.76 A recent study of DKD patients showed the overexpression of SUV39H1 and H3K9me3, with reduced renal inflammation and apoptosis, suggesting that SUV39H1 may be a protective target for the treatment of DKD.77 Further research should be conducted to test whether the overexpression chromatin marker, such as H3K9me3, could be used as a marker indicating the progression of DKD. In two rodents models of type 1 diabetes, OVE26 mice and streptozotocin rats, the levels of H3K4m2, a histone methylation activating mark, are increased, while the levels of H3K27m3, a repressive mark, are reduced in key genes, such as Mcp-1, vimentin and the fibrosis marker Fsp150, suggesting differential kidney gene expression in DKD is associated with aberrant histone methylation.

Histone crotonylation consists of the transfer of crotonyl groups to lysine residues of histones, that similar to acetylation, confers histones with negative charge.51,52 Lysine crotonylation (Kcr) has been considered as the conserved histone post-translational modification in the kidney.51 Nonetheless, the genomic pattern of histone crotonylation differs from histone acetylation.51 Histone crotonylation can activate or repress gene transcription in a gene- and/or environment-dependent manner.51 Recently, a potential role of histone Kcr was described in acute kidney injury (AKI).78 Most recently, the protective part of HDAC inhibitors in kidney diseases may be related to their role in crotonylation regulation, which could promote some nephroprotective genes, such as PGC1 and Sirt-3.79 This opens the door to explore therapeutic strategies based on the modulation of histone crotonylation.

Ubiquitin is a small, highly conserved 76 amino acid protein that can be covalently linked to lysine residues on histone and non-histone target proteins;80 And it targets the proteins for degradation through the ubiquitin proteasome system (UPS). Ubiquitination involves a multistep process mediated by an enzymatic cascade with ubiquitin ligases, including E1 activating enzymes, E2 conjugating enzymes, and E3 ubiquitin ligases. Studies found ubiquitination is widely involved in the occurrence of DN.81 The key step in Nuclear factor-kappa B (NF-B) activation is through ubiquitination of IB and NF-B dissociation, which plays a vital role in the expression of inflammatory cytokines related to DN. As previously reported, ubiquitination is involved in the progression of DN through activating NF-B, TGF- by degrading the related signal proteins. Most recently, a study in vitro and vivo suggested the tripartite motif-containing (TRIM13, a well-defined E3 ubiquitin ligase) promoted ubiquitination and degradation of C/EBP homologous protein (CHOP, associated with renal injury), which attenuated DN-induced collagen synthesis and restored renal function.82 This finding provides new insights into the application of histone ubiquitin in the treatment of diabetic nephropathy. Based on existing literature and studies, additional research is required to expose the hidden targets of histone ubiquitination to prevent DN.

Nephrin, a critical podocyte membrane component, has been shown to activate phosphotyrosine signaling pathways in human podocytes, then reduce cell death induced by apoptotic stimuli. High glucose and diabetes result in upregulation of SH2 domain-containing phosphatase 1 (SHP-1) in podocytes, thereby contributing to nephrin dephosphorylation and podocyte apoptosis.83 Additionally, an increased level of SHP-1 was also found in diabetic mice, causing decreased nephrin phosphorylation, which may lead to diabetic nephropathy. Another enzyme, Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is the source of reactive oxygen species in hyperglycaemia; Especially when phosphorylation of the cytosolic components of NOX, the development of oxidative stress worsens the kidney in a series of stages.84 Accordingly, investigating phosphorylation targets may benefit patients with diabetic kidney disease.

Some studies investigated in peripheral blood cells have included histone modifications in type 2 diabetics.85,86 Additionally, histone modification variations have been shown in human monocytes cultured under high glucose at a genome-wide level.87 However, plasma levels may not reflect their status in tissues and the cell nucleus.88 Therefore, further epigenome-wide studies in tissues from T2D patients are needed, especially in single-cell analyses. In some cases, histone acetylation and methylation are in a similar pattern and it is difficult to discern the specific contribution of each histone modification to gene expression differences.57 Although the overall profile of histone methylation in DKD has not been fully described, there is still information on individual modifications and genes.

Diabetic kidney disease is one of the major complications caused by persistent hyperglycemia.85,89 Inflammation and fibrosis are the two main factors implicated in the development of DKD. In this section, we focus on the roles of histone acetylation and methylation in the regulation of inflammation and fibrosis in DKD. Generally, ROS is considered to activate nuclear factor-kappaB (NF-B), resulting in a series of inflammation responses.90 NF-kB, a transcription factor, is involved in diabetic complications. Bierhaus et al91 confirmed that hyperglycemia induces activation of NF-kB, then activates its downstream target molecules such as adhesion molecules (monocyte chemoattractant protein-1 [MCP-1]),92 also known as chemokines CCL2, which participate in the pathogenesis of DKD. Pro-inflammatory cytokines and adhesion molecules are also activated by NF-kB. ROS-mediated inflammatory signaling regulated by lysine methyltransferase SETD7 was observed in an experiment conducted by He et al.93 Previous work has demonstrated that SET9 promotes ECM deposition in fibrosis.94,95 SET9 is shown to be recruited to the -SMA gene, and SET9 inhibition to treat CKD.96 In diabetic mice, high-glucose conditions increased the expression of Set7 and NF-B; both were related with elevated ROS production.97 These findings suggest that histone modifications mediated by ROS are involved in the inflammatory reaction of DKD. Likewise, high blood glucose levels (>15 mM) of stimuli such as TGF- have been implicated in the pathogenesis of DKD due to the adverse influence in renal cells.98100 A body of evidence has shown that TGF--mediated histone modifications are correlated with the development of DKD.101104

Many studies have demonstrated that under high glucose and TGF-1-induced conditions, profibrotic cytokines associated with diabetic nephropathy can be regulated by histone acetylation. Significant induction of PAI-1 and p21 mRNA in TGF-1 treatment of RMCs was associated with elevated H3K9/14Ac levels and overexpression of CREB-binding protein (CBP) or p300 at PAI-1 and p21 promoters. Meanwhile, high-glucose treatment increased H3K9/14Ac at TGF-1-inducible genes PAI-1 and p21 (the key players in DN) in rat renal mesangial cells. Furthermore, increased expression of PAI-1 and p21 in glomeruli from diabetic mice was also associated with elevated levels of promoter H3K9/14Ac, demonstrating abnormal histone acetylation in gene regulation both in vivo and vitro relevance to DN. A previous experiment in human renal proximal tubular epithelial cells (RPTEC) showed that epithelial-to-mesenchymal transition (EMT) induced by TGF-1 could be suppressed by TSA, an HDAC inhibitor.103

CHIP assays from glomeruli of diabetic mice also showed that increased expression of PAI-1 and p21 was related to the enrichment of H3K9/14Ac at their gene promoters.59 Conversely, co-transfection experiments confirmed that the overexpression of HDAC1 and HDAC5 could suppress TGF--induced gene expression (PAI-1 and p21). These studies suggest a key role of histone acetylation in the pathogenesis of gene expression and provide further therapeutic targets for DKD. In another study with a type 1 diabetes mouse model, significantly increased levels of connective tissue growth factor (CTGF), plasminogen activator inhibitor (PAI-1), and fibronectin (FN-1) in the kidney were related to increased HAT activity and enrichment of H3K9/14Ac and HAT p300/CBP at the CTGF, PAI-1, and FN-1 gene,60 suggesting a relationship between histone acetylation and renal fibrosis, which may provide a precise mechanism of glomerulosclerosis and interstitial fibrosis to prevent the development of DKD. It is well established that DKD is characterized by the accumulation of extracellular matrix (ECM) proteins including collagen, laminin, and fibronectin. Some evidence shows that the transcription of ECM proteins is regulated by epigenetic histone modifications. Fibroblasts incubated with TGF- revealed that elevated histone acetyltransferase activity of p300 and histone H4 acetylation accelerated COL1A2 expression.105 Interestingly, research in mice with diabetic kidney disease showed that high glucose induces the expression of myocardin-related transcription factor A (MRTF-A), which could activate collagen transcription. Further analysis revealed that MRTF-A recruited p300 and WD repeat-containing protein 5 (WDR5), an important component of histone H3K4 methyltransferase, to the collagen promoters, eventually leading to its gene expression.106 MRTF-A silencing makes acetylated histone H3K18/K27 and trimethylated histone H3K4 disappear and diminishes diabetic tubulointerstitial fibrosis.107 This study indicates that MRTF-A-associated histone modifications might provide a novel mechanism against DN-associated renal fibrosis. In another study, mice with streptozotocin-induced diabetic kidney disease showed low expression of the histone deacetylase SIRT1, and increased albuminuria. However, overexpression of SIRT1 in renal tubular could induce hypermethylation of the Cldn1 gene (the tight junction protein) and then prevented albuminuria.108 On the other hand, proximal tubule-specific deletion of Sirt1 in mice showed increased albuminuria related with reduced Cldn1 methylation, increased histone acetylation, and upregulation of Claudin-1.108 Thus, it can alleviate renal fibrosis with reduced albuminuria. These studies show the protective effects of SIRT1 in DKD and can further as a therapeutic target for DKD with in-depth evaluation. In rat DKD, the HDAC inhibitors trichostatin A (TSA) and valproic acid (VPA) were protective. TSA blocked extracellular matrix accumulation by TGF-1-induced. And it is thought to increase E-cadherin expression through HDAC inhibition, leading to increased acetylation of E-cadherin promoter, but it is unclear the mechanism on TGF-1 expression.102 HDAC 2/4/5/9 have been shown to be upregulated in kidney biopsy tissue obtained from patients with diabetes. More specifically, the mRNA level of HDAC2/4/5 was negatively correlated with eGFR in patients with DKD. Noh et al102 also reported that markedly increased HDAC-2 activity was proved in kidneys of diabetic rats and rat tubular epithelial cells. New observations demonstrate diabetes and TGF-1 could activate HDAC-2 in the kidneys, eventually involving the accumulation of ECM and EMT, and EMT has been reported to cause podocyte loss.109111 Podocytes stimulated by harmful factors such as high glucose, advanced glycation end products, and transforming growth factor- showed high expression of HDAC4. However, renal injury was alleviated by silencing the HDAC4 gene.112 After in-depth studies, Wang et al reported that inhibition of autophagy and increasing renal inflammation were associated with the effects of HDAC4112. In vivo gene silencing of HDAC4 ameliorated renal injury in STZ-induced diabetic rats, as evidenced by reduced albuminuria, ameliorated podocyte injury and mesangial expansion.113 Hence, HDAC4 plays a critical role in regulating the pathogenesis of DKD as an epigenetic mediator. Cultured murine proximal tubular cells treated with TGF-1 also showed protective effects through treatment with PCI34051 (a highly selective inhibitor of HDAC8) or HDAC8 siRNA, suppressing EMT.114 All of the above indicates that HDAC changes influence the progression of DKD, which may promote renal fibrosis and EMT. In view of individual HDAC isoforms playing different roles, additional studies are needed to clarify the relationship between renal fibrosis and histone acetylation and deacetylation, further giving a therapeutic target for individual patients with DKD.

In the Diabetes Control and Complication Trial (DCCT), the progress of microvascular results in the long-term Epidemiology of Diabetes Intervention and Complication (EDIC) studies showed that the hyperacetylation promoter (P < 0.05) in the top 38 cases contained more than 15 genes related to the NF-B inflammatory pathway and rich in genes related to diabetic complications.114 Preliminary work in endothelial cells showed that the sustained expression of p65 was associated with enrichment in Set7 and H3K4me1 on the p65 gene promoter, although cultured in transient hyperglycemia, and changes will always exist, even if returning to normoglycemia.71,115 The study highlighted that short-term hyperglycemia could have long-lasting effects on gene expression through epigenetic histone modification. Evans et al116 reported that stress-activated protein kinases stress pathways such as the NF-B, p38 MAPK, and kinases resulted in late diabetic complications. The first study of human blood monocytes showed that, under diabetic conditions, increased levels in acetylation of histones H3K9/14Ac and H4K5, 8, and 12Ac at the promoters of inflammatory genes such as TNF- and COX-2 led to gene transcription.117 Another study in advanced diabetic kidney disease mice after unilateral nephrectomy showed significantly increased global renal histone H3K9 and H3K23 acetylation, whereas CCL2 antagonist not only reversed histone acetylation abnormalities but also alleviated the progression of diabetic kidney disease.57 These studies demonstrated that histone acetylation under diabetic conditions is involved in the pathogenesis of DKD, which was associated with the continuous expression of the inflammatory gene. HDAC1 is downregulated both in Akita mice and in rat glomerular mesangial cells exposed to high glucose, resulting in overexpression of inflammatory gene through histone hyperacetylation.118 In another study, elevation of RNA polymerase II recruitment and H3K4me2 was found but decreased repressive H3K27m3 markers at the MCP-1 gene were observed in an OVE26 mice model of T1DM instead of in rat models, which eventually contributed to the increased expression of MCP-1 in a mouse model.119 The difference between rats and mice suggests that individual differences in epigenetics also need to be taken into account when translating into human DKD.

Under normal and high-glucose conditions, histone methylation is associated with TGF--1-mediated ECM gene expression, such as Colla1, plasminogen activator inhibitor-1 (PAI-1), and connective tissue growth factor (CTGF).120123

TGF-1 plays an important role that drives collagen myofibroblasts in injured kidneys and their signaling is also a key mediator in the expression of fibrotic and ECM genes involved in the pathogenesis of diabetic kidney diseases. In models of TGF-1-induced renal fibrosis, hypermethylation of Rasal1 promoter was induced by TGF-1, which increased fibroblast activation, and fibrosis.108 In another study of 18 in RMCs stimulated by TGF-1 showed not only the increasing recruitment of H3K4, HMT, and SET7/9 at ECM gene promoters but also in the expression of SET7/9. However, knockdown of SET7/9 could decrease global H3K4me1 but not H3K4me2 or H3K4me3 levels, indicating SET7/9-mediated H3K4me1 could play an important role in ECM gene expression. Involvement of histone methyltransferase (HMT) SET7/9 in p21 gene expression related to cellular hypertrophy, which results in the pathogenesis of DN, has also been demonstrated both in glomeruli of STZ-induced rats and HG-induced RMCs.124 These studies suggest that SET7/9 could participate in renal fibrosis by regulating methylation of H3 lysine 4 at fibrotic gene promoters. Then, SET7/9 may be a potential target for fibrotic gene disorders, which could provide potential therapeutic targets for DKD.

H3K9me3 levels in vascular smooth muscle cells (VSMCs) and endothelial cells in diabetic db/db mice were lower than those in a control db/db group.125,126 They were consistent with the result of a study of RMCs stimulated by TGF-1, which were related to HG-induced upregulation of these fibrotic genes. It was found that in patients with diabetic kidney disease, H3K9me3 overexpression in renal tubules has been verified as a protective role by decreasing renal inflammation and apoptosis. Accordingly, more details should be researched in DKD with the methylation of H3K9 for new insights to delay the progression of DKD. Loss of H3K27me3, EZH2, and heightened UTX (also known as KDM6A, a histone demethylase) were detected in the human podocytes in glomeruli of DKD, which increased podocyte dedifferentiation and aggravated glomerular injury by regulating Jagged-1 overexpression.127 Increased expression of H3K27me3 demethylases accompanied by decreased levels of Ezh2 protein and H3K27me3 were observed in rodent models with diabetic kidney disease. In the same experiment, RMCs stimulated by TGF- showed that the reduction of H3K27me3 at the CTGF, Serpine1, and CCl2 gene promoters upregulated profibrotic and inflammatory gene expression.101 Moreover, in streptozotocin-diabetic rats and in podocytes cultured under a high glucose with the inhibition of EZH reduced H3K27me marks at the Pax6 promoter, and then promoting PAX6 expression and aggravating podocyte injury, oxidative stress and proteinuria.128 However, another report showed that high-glucose stimulation promoted EMT and significantly up-regulated EZH2 expression in renal tubular epithelial cells, which may participate in the development of DN.129 The existence of the above biases may be related to the balance of histone methylation in epigenetic processes. SUV39H1, another histone methyltransferase as repressive mark H3K9m3, has been observed downregulated in kidneys from streptozotocin mice and in mesangial cells under high glucose. Interestingly, overexpression of SUV39H1 decreased extracellular matrix production in mesangial cells, reducing the renal fibrosis.76,130

In experimental diabetic nephropathy, histone methylation was associated with severe glomerulosclerosis, albuminuria and glomerular filtration rate reduction and CCL2 antagonist prevented the histopathological damage, indicating a role for CCL2 or inflammation in epigenetic regulation.57

In vitro, endothelial cells cultured in transient hyperglycemia showed that an increase in p65 expression was correlated with elevated levels of H3K4me1 and SET7 at the p65 promoter, but there was no change in H3K4me2/3.115,126 In the same study, EI-Osta et al115 indicated that sustained increase in monocyte chemoattractant protein 1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) were induced by activation of p65, both involved in the pathological process of DKD. HMT SET7 (the H3K4 methyltransferase) promotes the expression of inflammatory genes such as TNF-alpha in monocytes, which is a downstream inflammatory factor regulated by NF-B.131 These findings revealed the key role of HMT involved in mediating the expression of inflammatory genes related to DKD. Diminished H3K27me3 and increased expression of UTX were observed in glomerular podocytes from humans with glomerulosclerosis or DKD, whereas inhibition of UTX alleviated the established glomerular injury in db/db mice; UTX was recently found overexpressed in DKD patients and an elevated level of UTX and reduced H3K27me2/3 were also observed in db/db mice. Further studies to reveal the role of UTX in DKD showed that the transcriptional activation of inflammatory genes is mediated by UTX through removing H3K27me3 from these gene promoters.131 These results suggest the pathogenesis of DKD is associated with histone methylation and inflammation in the process could be regulated by histone methylation. Although TGF- is considered the key cytokine in contributing to fibrosis,132 the suppressed expression of matrix metalloproteinase 9 (MMP9) could also alleviate pathological conditions of early diabetic kidney disease,133 such as mesangial expansion, proteinuria, and podocyte foot effacement in the early stage of diabetic kidney disease. The decreased expression of lncRNA growth arrest-specific transcript5 (GAS5) and matrix metalloproteinase 9 (MMP9), a key inflammatory protein associated with DKD pathogenesis, was shown in a rat model with diabetic kidney disease. ChIP assays demonstrated that dramatic enrichment of EZH2 (a methyltransferase that induces histone H3 lysine 27 trimethylation) after overexpression of GAS5 could also elevate H3K27me3 as well as EZH2 to the promoter region of MMP9, leading to downregulated MMP9 expression and attenuating early diabetic kidney injury.134 The experimental data provide a promising target for DKD in the GAS5/MMP9 regulatory mechanism. EZH2 treatment can also impede the progression of DN. However, elevated recruitment of RNA polymerase II and H3K4me2 but decreased repressive H3K27m3 markers at MCP-1 genes were observed in a mouse model of T1DM instead of in male Sprague-Dawley rat models, which eventually contributed to increased expression of Monocyte chemoattractant protein-1 (MCP-1) in a mouse model.119 The difference between rats and mice suggests that individual differences in epigenetics also need to be taken into account when translating into human DKD.

A single histone modification does not always function in isolation. There is a complex interplay of indistinct histone modification. As previously mentioned, increased expression of pro-fibrotic genes (Colla1, PAI-1, and CTGF) induced by TGF1 and high glucose were enriched with active histone methylation markers, H3K4me, and histone acetylation markers H3K9/14ac at their promoters, hence their co-modifications may lead to more transcription of pro-fibrotic genes. Similarly, H3K18/K27ac and H3K4me3 recruited to the collagen promoters participate jointly in renal fibrosis of DKD.107 In other DKD experimental mice, increased histone acetylation (H3K9 and H3K23) and histone methylation (H3K4 dimethylation) were associated with progressive glomerulosclerosis,57 so these co-expressed chromatin markers can provide a useful signal to indicate advanced diabetic nephropathy, which could support clinicians to provide individualized treatment for patients. Considerable evidence has suggested that injured kidneys increased the expression of DOT1L and H3K79 dimethylation, particularly in renal tubular epithelial cells and myofibroblasts, eventually aggravating renal fibrosis, even developing end-stage renal disease. However, emerging evidence by Zhang et al135 showed that Dot1l has an antifibrotic effect. Using several approaches in groups of mice, Dot1a-HDAC2 complex regulated H3K79me2 and H3 acetylation at the endothelin 1 (Edn1) promoter, ensuring the balance of endothelin transcription. This could represent a new mechanism between Dot1a and HDAC2 in modulating kidney fibrosis.

Some epigenetic drugs focus on cancer, neuronal diseases, hematological diseases and inflammatory disease,136,137 such as HDAC inhibitors.138 HDAC inhibitors were used for the modulation of insulin signaling and -cell functioning,139,140 as it could release the glucose transporter 4, GLUT4,141 and then transfers the glucose from the outside cell to the inside of the cell, avoiding producing a series of harmful factors to the kidney. The class III HDAC protein, SIRT1, plays a protective role in the upregulation of the antioxidant gene in glomerular mesangial cells.142 In diabetic OVE26 mice, administration of the SIRT1 agonist BF175 attenuated podocyte injury.143 However, HDAC inhibitors were generally non-specific; Hence, it may be valuable to develop more selective inhibitors or activators of HDACs. Meanwhile, considering safety and specific populations that may benefit from epigenetic interventions, there is not yet enough information. Accordingly, more clinical trial stages should be target epigenetic modifications in DKD. The most tough and unresolved but critical issue is to define the tissue-specific relative contributions of epigenetic writers and erasers; It has been shown HDAC3 deletion from the macrophage is vasculo-protective,144 while deletion of the HDAC3 from endothelial cells aggravates the macrovascular disease.145 Recently, whereas HDAC9 is a protective target for Medial artery calcification (MAC) in CKD patients,146 overexpression of the same enzyme in diabetic nephropathy exacerbates podocyte injury.147 In the future, Genome editing via CRISPRCas9 and other methods148151 will be a strong method to modify epigenetic changes, benefiting from its locus-specific epigenetic modification, eventually improve the efficacy of pharmacological therapy.

The pathogenesis of DKD is complicated with interactions between injury factors, growth factors/cytokines, and metabolic products. The epigenetic mechanism can integrate these connections to mediate the development of DKD. With accumulating investigations in both animals and renal cells, as well as the data from clinical diabetes patients, as previously described, we can conclude that metabolic memory exists in DKD. Histone modifications and DNA methylation participate in DKD-associated gene expression, including fibrotic and inflammatory genes (Figure 1). The epigenetic mechanism provides an insight to thoroughly understand the DKD mechanism. Cellular heterogeneity and individual differences were found in histone modifications, so the cell-type-specific gene expression affected by histone modifications makes it difficult to identify the stage of DKD progression in clinical patients, even using epigenome-wide association studies (EWAS). Overall, HDAC inhibitors may protect against fibrosis in diabetic kidney disease. However, this field remains challenging, since the enzymes have a broad substrate specificity and deacetylate many proteins that are not related to epigenetic regulation.136 Although these data indicate that histone acetylation and methylation may play a key role in altered gene expression during DKD, it is more necessary to specifically target individual enzymes function in vivo. The detailed analysis of DKD between histone modifications requires more in-depth research. For example, high glucose may induce more transcriptional factors that regulate DKD-associated genes with epigenetic histone modifications. Understanding the regulation of fibrosis by TGF- can help identify more potential antifibrotic targets, which could prevent or halt renal fibrosis in DKD. Exploring the precise pathological mechanisms in epigenetic histones and novel biomarkers is necessary to translate these preclinical findings into treatment strategies for DKD patients. Also, when single-cell epigenetic techniques are developed and together with currently available single-cell transcriptomics data, it can pinpoint the effect of certain histone post-translational modifications to a specific cell type or a specific molecule.

Figure 1 Schematic representation of histone modifications in diabetic-induced fibrotic and inflammatory gene expression. High-glucose conditions cause the expression of ECM-associated genes Col1a1, CTGF, PAI-1, FN-1, Lacm1, and P21 as well as inflammatory genes TNF-, COX-2, and MCP-1, leading to fibrosis and glomerulosclerosis in the pathogenesis of DKD. The gene expression is based on the increased active chromatin markers (H3K4me, H3K9/14ac, and H3K79me) and decreased repressive markers (H3K9me3 and H3K27me3) on the promoters of fibrotic and inflammatory genes. Under diabetic conditions (high glucose), TGF- antibodies, some specific HDACs, TSA, and antioxidants could have renoprotective effects.

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

This study was funded by research grants (81870500 and 81770692) from the National Natural Science Foundation of China. It was also supported by the Hunan Provincial Clinical Medical Technology Innovation Guide Project (S2020SFYLJS0334).

The authors report no conflicts of interest in this work.

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[Full text] Epigenetic Histone Modifications in the Pathogenesis of Diabetic Kidne | DMSO - Dove Medical Press

While eyesight often dims with age, a novel mouse study provides intriguing evidence that innovative gene therapy techniques could someday roll back the biological clock for our vision. The research was conducted with NIA and the National Eye Institute support by a Harvard Medical School team and published recently in Nature.

The teams approach involved epigenetics, a field of science that studies heritable changes that can activate or deactivate genes without any change in the underlying DNA sequence of these genes. The word epigenetics is of Greek origin and literally means over and above (epi) the genome.

Their experiments refined a technique that won a Nobel prize in 2012. The basic idea is that by using a harmless virus to introduce just a few genes, called Yamanaka factors after the researcher who discovered them, scientists can reprogram the DNA of mature cells of different types to transform back into young (pluripotent) stem cells. These can then regenerate function lost to age, illness, or injury. The virus payload is turned on or off via injection of a selective inducer molecule.

This cell reprogramming method could lead to future disease therapies, but previous studies showed it is tough to safely rein in the rapid cell growth and tumor development triggered by Yamanaka factors. The Harvard team found a way to keep the beneficial effects and weed out the dangerous ones by leaving out one of the four factor genes, called MYC, that is closely related to cancer and can shorten the lifespan of mice when it is expressed.

First working in lab cell cultures, the team was able to rejuvenate damage to retinal ganglion cells, a type of neuron found at the rear of the eye. Later in a mouse model, the same techniques seemed to protect some optic nerve cells from damage and caused others to grow fresh connections to the brain. A third experiment had similar success reversing some vision damage in a mouse model of glaucoma, a leading cause of age-related blindness in humans.

In lab tests, the glaucoma model mice who received the injection treatment gained back roughly half of their previously lost visual ability. In other experiments, middle-aged mice who received the injection scored similar to younger mice in visual tests, plus their DNA showed expression and methylation (epigenetic patterns of common chemical groups that attach to DNA at different life stages) signatures that resembled the genetic material of younger mice. They have also found that these recovered functions require two DNA methylation enzymes that could be responsible for these epigenetic changes during the reprograming.

While the researchers are encouraged by this progress, they caution that epigenetic reprogramming techniques are still very complex and still harbor risk of abnormal cell growth or cancer. They plan to conduct many further studies to test the gene therapy technologies in larger animals, explore how the restorative factors impact other types of cells and tissues, and verify that the youthful changes seen are not fleeting.

This research was funded by NIA grants R01AG019719, R37AG028730, R01AG067782, R01AG065403, K99AG068303, and T32AG023480.

Reference: Lu Y, et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020;588(7836):124-129. doi:10.1038/s41586-020-2975-4

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Gene therapy techniques restore vision damage from age and glaucoma in mice - National Institute on Aging

GLOBAL EPIGENETICS-BASED INSTRUMENTS MARKETIS EXPECTED TO REGISTER A SUBSTANTIAL CAGR IN THE FORECAST PERIOD OF 2019-2026. THE REPORT CONTAINS DATA FROM THE BASE YEAR OF 2018 AND THE HISTORIC YEAR OF 2017. THIS RISE IN MARKET VALUE CAN BE ATTRIBUTED TO THE VARIOUS INNOVATIONS AND ADVANCEMENTS OF TECHNOLOGIES ASSOCIATED WITH EPIGENETICS.

The market data included in this Epigenetics-Based Instruments report helps businesses to successfully make decisions about business strategies to achieve maximum return on investment (ROI). All this data and information is very significant to the businesses when it comes to define the strategies about the production, marketing, sales, promotion and distribution of the products and services. This report suits your business requirements in many ways and also assists in informed decision making and smart working. With the Epigenetics-Based Instruments report it can also be analysed that how the actions of key players are affecting the sales, import, export, revenue and CAGR values.

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Few of the major competitors currently working in the global epigenetics-based instruments market arePacific Biosciences of California, Inc.; 10x Genomics; Illumina, Inc.; Merck KGaA; QIAGEN; Eisai Co., Ltd.; Novartis AG; Diagenode s.a.; Zymo Research; Active Motif, Inc.; Thermo Fisher Scientific Inc.; Agilent Technologies, Inc.; Bio-Rad Laboratories, Inc.; Bio-Techne among others.

Key Developments in the Market:

Market Drivers

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Segmentation: Global Epigenetics-Based Instruments Market

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Global Epigenetics-Based Instruments Market Size, Status and Forecast 2019-2026||QIAGEN; Eisai Co., Ltd.; Novartis AG; Diagenode sa; Zymo Research;...

An analysis report published by DataIntelo is an in-depth study and detailed information regarding the market size, market performance and market dynamics of the Epigenetics. The report offers a robust assessment of the Epigenetics Market to understand the current trend of the market and deduces the expected market trend for the Epigenetics market for the forecast period. Providing a concrete assessment of the potential impact of the ongoing COVID-19 in the next coming years, the report covers key strategies and plans prepared by the major players to ensure their presence intact in the global competition. With the availability of this comprehensive report, the clients can easily make an informed decision about their business investments in the market.

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This detailed report also highlights key insights on the factors that drive the growth of the market as well key challenges that are expected to hamper the market growth in the forecast period. Keeping a view to provide a holistic market view, the report describes the market components such as product types and end users in details with explaining which component is expected to expand significantly and which region is emerging as the key potential destination of the Epigenetics market. Moreover, it provides a critical assessment of the emerging competitive landscape of the manufacturers as the demand for the Epigenetics is projected to increase substantially across the different regions.

The report, published by DataIntelo, is the most reliable information because it consists of a concrete research methodology focusing on primary as well as secondary sources. The report is prepared by relying on primary source including interviews of the company executives and representatives and accessing official documents, websites, and press release of the companies. The DataIntelos report is widely known for its accuracy and factual figures as it consists of a concise graphical representations, tables, and figures which displays a clear picture of the developments of the products and its market performance over the last few years.

Furthermore, the scope of the growth potential, revenue growth, product range, and pricing factors related to the Epigenetics market are thoroughly assessed in the report in a view to entail a broader picture of the market.

Key companies that are covered in this report:

IlluminaThermo Fisher ScientificMerck MilliporeAbcamActive MotifBio-RadNew England BiolabsAgilentQiagenZymo ResearchPerkinelmerDiagenode

*Note: Additional companies can be included on request

The report covers a detailed performance of some of the key players and analysis of major players in the industry, segments, application and regions. Moreover, the report also takes into account the governments policies in the evaluation of the market behavior to illustrate the potential opportunities and challenges of the market in each region. The report also covers the recent agreements including merger and acquisition, partnership or joint venture and latest developments of the manufacturers to sustain in the global competition of the Epigenetics market.

By Application:

OncologyMetabolic DiseasesDevelopmental BiologyImmunologyCardiovascular DiseasesOther Applications

By Type:

DNA MethylationHistone ModificationsOther Technologies

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According to the report, the Epigenetics market is projected to reach a value of USDXX by the end of 2027 and grow at a CAGR of XX% through the forecast period (2020-2027). The report covers the performance of the Epigenetics in regions, North America, Latin America, Europe, Asia Pacific, and Middle East & Africa by focusing some key countries in the respective regions. As per the clients requirements, this report can be customized and available in a separate report for the specific region and countries.

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Executive Summary

Assumptions and Acronyms Used

Research Methodology

Epigenetics Market Overview

Epigenetics Supply Chain Analysis

Epigenetics Pricing Analysis

Global Epigenetics Market Analysis and Forecast by Type

Global Epigenetics Market Analysis and Forecast by Application

Global Epigenetics Market Analysis and Forecast by Sales Channel

Global Epigenetics Market Analysis and Forecast by Region

North America Epigenetics Market Analysis and Forecast

Latin America Epigenetics Market Analysis and Forecast

Europe Epigenetics Market Analysis and Forecast

Asia Pacific Epigenetics Market Analysis and Forecast

Middle East & Africa Epigenetics Market Analysis and Forecast

Competition Landscape

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Global Epigenetics Market by Trends, Dynamic Innovation in Technology and Key Players| Illumina, Thermo Fisher Scientific, Merck Millipore, Abcam,...

The Fountain of Youth -- an enduring aspiration, particularly as the ravages of age reduce human faculties prior to leading inexorably to death. Reduction in sight is the human faculty that can have the greatest effect on quality of life in the aged -- a faculty that begins to decline in the 4th or 5th decade of life and doesn't get better (when it does) without medical intervention.

But what if there were a way to rejuvenate sight? That prospect is the tantalizing suggestion in a paper published on December 2nd entitled "Reprogramming to recover youthful epigenetic information and restore vision," Nature 588: 124-29*. The basis of the report is the recognition that many of the age-related effects on vision are an example of gene expression differences associated with epigenetic changes in chromosomal DNA. Epigenetics is a phenomenon of gene structure and expression involving small differences in nucleotide bases, typically methylation of cytosine residues at specific (CpG) sites. These changes have been studied in normal development, where gene expression changes arise as different cell types properly differentiate and act as a molecular "clock" reflecting age. The ability to turn back cellular time has been demonstrated by the development of induced pluripotent stem cells (iPSCs), wherein terminally differentiated somatic cells (typically fibroblasts) can be turned into pluripotent cells. Pluripotent cells are capable of differentiating into cells of each embryonic germinal layer (ectoderm, mesoderm, endoderm), and iPSCs can be produced by expressing four specific genes: OCT4, SOX2, KLF4 and MYC. All of these genes encode transcription factors capable of affecting (and effecting) developmentally relevant gene expression. Consequent to this "de-differentiation" occasioned by expression of these genes is a "resetting" of the epigenetic patterns associated with development. In this paper the researchers hypothesized that resetting these epigenetic patterns could also rejuvenate neuroretinal cells to reinvigorate and overcome the ocular nerve damages by glaucoma in an animal model.

Because one of these genes (MYC) is also associated with cancer development (i.e., it is an oncogene) the researchers developed an inducible expression construct that expressed only the OCT4, SOX2, and KLF4 members of the quartet (OSK). (This decision was also informed by the experience of other researchers that continuous expression of all four genes in animal models resulted in teratomas or was fatal within days of introduction.) Their system used a polycistronic (i.e., all the genes in one linear array) construct of all three genes regulated by a tetracycline response element (TRE) promoter in a adeno-associated viral vector. This construct was tested by introduction into fibroblasts from aged (20 month old) mice and gene expression related to aging (i.e., that showed differential expression with age) was evaluated. These studies showed that OSK expression for 5 days resulted in a "youthful" mRNA expression pattern in these genes (without any effect on the terminal differentiation state of the fibroblasts).

The TRE promoter enabled selection for or against expression of the OSK gene cassette; as the authors explain "[t]he TRE promoter can be activated either by reverse tetracycline-controlled transactivator (rtTA) in the presence of the tetracycline derivative doxycycline (DOX) ('Tet-On') or by tetracycline-controlled transactivator (tTA) in the absence of DOX ('Tet-Off')." Simply put, the presence of absence of DOX in the animal's drinking water determined whether the expression cassette is "on" or "off," as illustrated in this figure:

Long-term (10-18 months) expression of this cassette was achieved in both young (5 months-old) and aged mice with no tumorigenesis or other negative side effects being observed.

To test the ability of induced OSK expression to rejuvenate optical nerve cells the researchers examined retinal ganglion cells (RGC, which project axons away from the retina informing the optic nerve) in an optic nerve crush injury model (which mimics the effects of optic nerve injury due to inter alia glaucoma). The construct was delivered by injection into the vitreous humor and resulted in about 37% of the RGCs taking up and expressing the OSK genes in response to DOX administration. A separate cohort of mice were administered versions of the construct where DOX inhibited OSK expression. In these experiments, "the greatest extent of axon regeneration and RGC survival occurred when all three genes were delivered and expressed as a polycistron within the same AAV particle" according to the researchers. In contrast, inhibition of OSK expression in the "Tet-Off" mice showed no axonal growth. Moreover, delivery of the OSK genes individually in separate viral vectors or in pairs also did not show axonal growth, indicating the need for these genes to be expressed together in proper relative amounts provided by the polycistronic construct. The researchers also found OSK expression induced expression of Stat3, a gene know to encourage regeneration. These results were obtained in using 12-month-old mice as well as 1- and 3-month-old mice, which indicated, as the authors note, that "ageing does not greatly diminish the ability of OSK transcription factors to induce axon regeneration." Increased axonal growth from RGCs was found even after crush injury, an effect found with no other treatment modalities.

The researchers then determined whether these reinvigorated RGCs showed changes in DNA methylation patterns. In the absence of DOX-induced OSK expression injury in this model caused an "accelerated" aging pattern, whereas in the presence of DOX-induced OSK expression counteracted this effect according to the results reported in this paper. Interestingly, this preservation of a "youthful" pattern of DNA methylation was found to be enriched at genes "associated with light detection and synaptic transmission." Having shown this association the researchers then investigated whether axonal regeneration required youthful changes in DNA methylation. These experiments were performed by reducing expression of genes that caused DNA demethylation in RGCs (and whose expression was known to be increased in cells expressing OSK) and detecting that axonal regeneration did not occur in these mice even in the presence of DOX-induced OSK expression.

Whether these effects of OSK expression would also be seen in human neurons was investigated using differentiated human neurons in vitro. Neurons harboring an OSK-encoding construct were treated with vincristine (a drug that occasions axon injury) and DOX-induced OSK expression was shown to "counteract[] axonal loss and the advancement of DNA methylation age," showing a 15-fold greater area of proliferation in OSK-expressing cells than control vincristine-treated neural cells. These cells also showed the demethylation-dependent characteristics that were shown in RGCs in the mouse optic nerve crush injury model.

The most clinically significant result disclosed in this paper involved the effect of OSK expression in a glaucoma model in vivo. Intraocular pressure was increased to pathological levels by injecting microbeads unilaterally into the anterior chamber of mouse eye for 21 days. At 4 weeks, after these animals showed correspondingly unilateral decreases in axonal density and the number of RGCs present in the treated eye. The viral vector encoding inducible OSK expression thereafter was introduced by intravitreal injection followed by DOX-induced OSK expression for 4 weeks. Compared with control (introduction of saline or viral vectors not encoding OSK into the microbead-treated eyes) the OSK vector-treated eyes showed "restored axon density equivalent to that in the non-glaucomatous eyes, with no evidence of RGC proliferation." These mice also showed a reversal of vision loss caused by the glaucomatous injury. Together these results indicated that OSK expression could be a therapy for glaucoma in humans.

Finally, the paper reports efforts to determine whether OSK expression could improve age-related (as opposed to injury- or pathology-related) vision problems. In these experiments, 3-and 11-month-old mice were treated by intravitreal injection of DOX-inducible OSK encoding constructs and OSK expression induced for 4 weeks. Twelve-month-old mice showed age-related visual acuity and RGS electrical activity diminution which was reversed by DOX-induced OSK expression. However, these phenotypic changes were not observed to be associated with an increased number of RGCs or axon density, which prompted these researchers to hypothesize that the effect were dependent on changes in gene expression ("transcriptomic changes" as these were termed in the paper). RGCs from treated or untreated 12-month-old mice were isolated and compared with RGCs from 5-month-old mice and expression of 464 genes were found to be altered: expression of almost all (90%) of these genes were found to be restored to youthful levels in OSK-expressing RGCs. The participation of DNA methylation changes in aged RGCs in producing a youthful pattern of gene expression was further assessed and validated using artificial intelligence/machine learning approaches.

The results reported in this paper suggest therapeutic interventions that could improve vision in the aged human population even in the absence of vision-impairing pathologies such as glaucoma. Although cautious to mention that "we do not wish to imply that DNA methylation is the only epigenetic mark involved in this process" and "[i]t is likely to involve other transcription factors and epigenetic modifications," the authors are not blind to the implication that:

[W]e show that it is possible to safely reverse the age of a complex tissue and restore its biological function in vivo. Using the eye as a model system, we present evidence that the ectopic expression of OSK transcription factors safely induces in vivo epigenetic restoration of aged CNS neurons, without causing a loss of cell identity or pluripotency. Instead, OSK promotes a youthful epigenetic signature and gene-expression pattern that causes the neurons to function as though they were young again. The requirement for active demethylation in this process supports the idea that changes in DNA methylation patterns are involved in the ageing process and its functional reversal.

* By researchers from Harvard Medical School, Yale University School of Medicine, Massachusetts General Hospital, UCLA Geffen School of Medicine, and The University of New South Wales Medical School.

Excerpt from:
Epigenetic Changes Implicated in Age-related Diminution in Vision and Its Possible Reversal - JD Supra

Drought costs farmers around the world 10bn in crop losses every year but new trial results show that combining biostimulants with micronutrients could be the answer to food security.

The study, by researchers at Nottingham Trent University in collaboration with Micromix, looked at the effect of a hybrid biostimulant with nutrients on drought and heat tolerance in a range of crops. It found that the product changed the plants response to stress, increasing drought tolerance by 25-35% and boosting yields by up to 30%.

This is really game-changing it could offer a big contribution to global food security, says Chungui Lu, Professor of sustainable agriculture at the University. In the UK alone, we could save millions of Pounds in lost crops.

Abiotic stress - due to extreme temperatures, water, salt and solar radiation - induce a metabolic and epigenetic change in a plant, weakening its natural defense mechanisms and increasing its susceptibility to disease, pests and subsequent crop failure, explains Prof Lu. Biostimulants have the potential to affect a plants response to this stress, stimulating its own natural processes, while micronutrients enrich its growing environment. This new formulation comprises a number of key nutritional materials, including micronutrients, in a novel combination with several biostimulant components, which will suppress abiotic stress and stimulate further growth.

The trial is the latest to be carried out on this new technology, after it produced remarkable effects under initial testing on protected salad and field crops in the Middle East, South East Asia and Europe. We realised we had accidentally discovered a new kind of synergy, and needed to validate it scientifically, says Wilson Boardman, founder at Micromix and product developer. In 2014, with Prof Lu, he secured a 247,000 Innovate UK research grant, through which they discovered that the key genes relating to heat tolerance were strongly upregulated by the new technology.

This 2014 trial focused on bell peppers, which are very heat sensitive at 28C they start to wilt and at 30C they stop growing. But the treated crops were still actively growing at over 30C, boosting yields by 20% and shelf life by 44%, alongside an improvement in fruit mineral content. This has directly led to important new discoveries in epigenetics and a further research project, says Prof Lu.

In 2018 Mr Boardman and Prof Lu secured an 807,948 Innovate UK grant to further investigate the genetic influence of the product. Prof Lu looked at a variety of crops, including wheat, peas, Pak choi and potatoes, and discovered specific genes which were triggered by the biostimulants, using plant genomic / transcriptomic technologies. This reduced the negative impact of stress and stimulated plant growth.

We identified 178 key genes that are affected by the new biostimulant technology, which provides insight into gene regulation and molecular markers for breeding programmes targeted at drought tolerance, says Prof Lu. This will have a big impact for agriculture, protecting against climate change and directly protecting crop growth and quality. For example, treated crops increased cutin formation and reduced respiration, preventing water loss, while also increasing some enzymes and defense activity, boosting nutrient transfer, growth and disease resistance.

Prof Lu plans to publish his scientific paper in early 2021, and will then apply for further grant funding to help develop the next generation of biostimulants. We want to design larger field trials across more crops, to identify the correct rate and timing of application for different crops.

Micromix plans to launch products based on the research to market in the next two years, although application techniques will be refined as the research continues. The University is really excited, says Prof Lu. It will be really good to do further research into improved crop quality. The outputs of the research will enable the successful commercialisation of novel farming systems, which will in turn help to improve food security, reduce the environmental impact of food production, create local employment and contribute to community health, wellbeing and sustainability.

For more information:Micromixwww.micromix.com

Read more:
Biostimulants fighting drought and heath - hortidaily.com

FERNANDINA BEACH, Fla., Dec. 9, 2020 /PRNewswire/ -- Ponce De Leon Health, Inc. ("Ponce de Leon"), a longevity research company focused on the reversal of epigenetic aging, announced today that Brian Kennedy, Ph.D., will speak at the SupplySide Network "Healthy Aging Never Gets Old" event on December 10th, 2020, at 1:00 PM Eastern.Doctor Kennedy is currently serving as Director of the Centre for Healthy Longevity, at the National University of Singapore.Registration for this free event can be found on theSupplySide Network 365platform.

Doctor Kennedy was invited to address industry leaders to discuss recent research which led to the development of Rejuvant LifeTabs, a dietary supplement designed for healthier aging. Informa Health & Nutrition named Rejuvant LifeTabs asthe top Consumer Packaged Goods winner in the Best Life-Span Specificcategory, at the 2020 NEXTY SupplySide Awards. According to Informa, Rejuvant contains "a ground-breaking ingredientLifeAKGand a meticulously researched, time-release formula tailored to men and women."

This news follows on the heels of Ponce De Leon Health announcement in September with the first peer-reviewed study of a non-drug substance demonstrating improvements in mammalian lifespan, reduction in frailty, and reduction in time of suffering. The results of the research were published in the September 1, 2020 issue of the journal Cell Metabolism. The researchers found that LifeAKG "promotes longer, healthier life associated with a decrease in levels of inflammatory cytokines. Strikingly, the reduction in frailty led the scientists to "propose that Ca-AKG compresses the period of morbidity." The publication, titled "Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice," and was authored by Azar Shamirzadi, Ph.D., et al., and directly led to the development of Rejuvant LifeTabs.

Tom Weldon, the CEO and Founder of Ponce De Leon Health, remarked, "We're very proud of our research, past and ongoing, and committed to reversing epigenetic aging. Our product, Rejuvant LifeTabs, is emblematic of the growing discoveries in the field of epigenetics, or the changes made by modification of gene expression.We continue to conduct new human and animal trials to better demonstrate the benefits of Rejuvant on biological aging, healthspan and lifespan."

Todd Runestad, Senior Editor of Ingredients and Supplements, New Hope Media and Natural Products Insider, invited Dr. Kennedy to speak at the event.Said Mr. Runestad, "healthy aging is a prime consideration of supplement usersfrom specific health conditions like bone or joint or cognitive health, to the more general concept of aging gracefully. Of course, people have long sought out skin-health products, but the new frontier is the provocative research around epigenetics and nutrigenomicsthat one's lifespan is not just predicated on genetics, but that gene expression can be modulated by diet and specific dietary supplements."

Mr. Runestad added, "Brian Kennedy has been researching such concepts for decades now. He is one of the world's leading anti-aging researchers, and he may have come up with this decade's resveratrolthe fountain of youth molecule found in red wine. We awarded a NEXTY award for the year's best innovation, integrity and inspiration, to a supplement brand Dr. Kennedy helped develop for Ponce de Leon Health. The company's Rejuvant LifeTabs, coupled with an in-home genetic test kit, allows consumers the ability to actually track over time genetic markers of aging while taking the supplement. Personalized health care meets anti-aging science."

About Ponce De Leon HealthPonce De Leon Health (www.PDLHealth.com) is a commercial-stage longevity company focused on the discovery, development and commercialization of non-prescription consumer products to address the reversal of epigenetic aging. Their goal is to increase human healthspan, improve quality of life, and reduce the cost of providing late stage health care to customers.

To learn more about the groundbreaking science behind Rejuvant LifeTabsvisit http://www.rejuvant.com or follow @rejuvanthealth(Facebook), @Rejuvant (Twitter), or Ponce De Leon Health (YouTube).

SOURCE Ponce De Leon Health

http://pdlhealth.com

See more here:
Leading Healthy Aging Researcher Brian Kennedy, Ph.D., To Address Natural Health Industry On Impact Of Nutrition On Biological Age - PRNewswire

Some of the below was reprinted with permission from World at Large, a news outlet focusing on space, health, conservation, environmental and foreign policy, and travel.

Researchers at Harvard Medical School have successfully restored vision loss and reversed glaucoma-induced damage in mice.

In the mice, the retinal ganglion cells, a principal cell that enables vision, were restored to a youthful state in cases of glaucoma, as well as when the optic nerve, another key component of eyesight, had been damaged. Both were achieved through expressing certain transcription factorsproteins that turn genes on and off.

The study sheds light on the mechanisms of ageing, and identifies new potential therapeutic targets for age-related neuronal diseases such as glaucoma, reads a statement from researchers at Harvard Medical School.

The new study, published in Nature, was conducted by Dr. David Sinclair, of the worlds foremost experts on ageing-related research in mice.

Along with genetic research, Sinclair has also looked at how supplement-ready compounds like resveratrol and Metformin affect aging, and his book, Lifespan: Why We Age and Why We Dont Have To, is a New York Times bestseller.

The science behind Sinclairsnew paper involves the curious process of methylation. Governed by epigeneticsthat is, changes in the genetic expression of the cell over timethe researchers found that methylation in mammalian tissues prevents the cells from replicating proteins properly while simultaneously encoding a kind of genetic history.

RELATED: 8-Year-old Sees Stars for the First Time After His Blindness is Treated With Gene Therapy

One can imagine this as scratches on the bottom of a CD. If the scratches could be removed, the record of proper function is still there, and could still be read by the laser in a CD player.

In his book, Sinclair details the modern theory of aging, which is that changes in epigenetics and damage to cells and tissues prevent the body from properly reading protein-encoding genes, resulting in either faulty, less-functional, i.e. older genes being transcribed, or the proteins not being replaced at all.

Here the authors found that when the mouse neurons were recovering from damage related to glaucoma, the methyl groups which built up over time left, like the scratches being removed from a disk.

This resulted in a process called demethylation. Demethylation was associated with younger genetic expression, in other words, the mouses genes remembered how to be young again, only after demethylation had occurred.

READ: First-of-Its-Kind Study Finds Shining a Red Light Through the Eyelid for 3 Minutes Per Day Can Boost Failing Eyesight

These data indicate that mammalian tissues retain a record of youthful epigenetic informationencoded in part by DNA methylationthat can be accessed to improve tissue function and promote regeneration in vivo, write the authors in their summary.

It remains to be seen whether records of youthful genetic expression are contained within other mammalian tissues, the liver for a random example, through methylation, and whether or not they can be accessed through demethylation.

MORE: Breakthrough App Guides Blind Runner on Solo 5k Run Through Central Park

If its true that simply altering some transcription factors is enough to clear the dust off the rule book for how to build young proteins, Sinclair stands to make a major breakthrough.

SHARE the News of This Exciting ResearchWith Friends

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Blind Mice with Glaucoma See Again Through Simple Technique that Promotes Youthful Gene Expression - Good News Network

Scientists have known since ancient times, as notable in Greek mythology, that liver tissue has a remarkable ability to regenerate, but embryologist Kim Tremblay, veterinary and animal sciences, says, We still dont know how it does that, its still a mystery even after two thousand years.

She now has a five-year, $1.4 million grant from the NIHs National Institute of Diabetes and Digestive and Kidney Diseases to investigate how the organ can replace itself in an amazingly short time. Unlike any of our other organs, if you cut out two-thirds of your liver, it will grow back in seven days, she says. Whats amazing about that time is that in many organisms that have a liver, it can grow back in seven days.

The liver filters impurities, toxins, alcohol and drugs, for example, from the bloodstream, which kills many cells, so in a sense its not surprising that the organ can quickly respond to injury by making new ones, Tremblay says. There is a reservoir of cells that replace the dead ones. The liver has a huge number of regenerative or homeostatic cues that trigger this, but we have not yet established which cells are responsible for this.

As a developmental biologist, Tremblay will focus on how hepatic cell types emerge during embryonic development. Using this strategy, she hopes to address long-standing disagreement in the field regarding the cells that are involved in regeneration. Some scientists think its one type, others insist it is another, she says, but the problem is that they are often using different regeneration models. What if adult cells are able to respond to distinct regenerative cues in unique ways because of where or how they arose in the embryo?

In the embryonic liver bud, she explains, embryonic precursor cells called hepatoblasts differentiate into two distinct adult cell types hepatocytes and cholangiocytes. Researchers have varying views about which of these might hold the regeneration key. We do know they arise in different developmental pathways in the embryo and they look different in an adult, Tremblay adds.

Her previous experiments in a culture system she developed show that hepatoblasts, the hepatic precursor cells, respond differentlyto cues growth factors and other signals in the embryo. Tremblay believes that a new series of investigations in a mouse liver model using targeted genetic techniques will show that both cell types harbor more than one as-yet-undiscovered variant.

I think we havent yet discovered the differences within those groups, the embryologist says. The grant is designed to explore this heterogeneity in development. Well use RNA transcript analysis from knock-out mice to identify the roles of particular genes, and well also explore ATAC-Seq. ATAC-Seq is a sensitive technique used to look for epigenetic memory, which is where Tremblay hypothesizes that her lab will find the key to how the different cells arise.

So far, the work in our lab has focused on the liver bud around 9.5 days of development, Tremblay says. In the future, we want to study the process later in development but still in the embryo.

By 10.5 days the liver is composed of hepatoblasts in lobes, and a slightly later cells start going down the path toward becoming hepatocytes or cholangiocytes. Thats when well look at the different RNA transcripts, but I think were going to find that the answer has to do more with epigenetics and the different environmental signals the precursors are exposed to. Because developmentally acquired epigenetic traits can be maintained through adulthood, it could provide a mechanism that would explain why some adult liver respond to certain injuries better than others.

Originally posted here:
Embryologist Kim Tremblay Will Explore the Secrets of Liver Regeneration - UMass News and Media Relations