Scientists from the University of Cambridge have determined the first 3D structures of mammalian genomes from individual cells.

For the first time, researchers from the University of Cambridge were able to determine the 3D structure of an active mouse genome in embryonic stem cells. Tim Stevens and his colleagues used a combination of imaging and measurements that reveal DNA interactionsto unravel how the DNA is folded together.This could lead tonew insights into the regulation of gene expression in health and disease.

Every cell in our body contains the same DNA molecules and thusthe same set of genes. Still,our blood cells differ fundamentally from our skin cells. The basis for this isgene regulation, meaning that different cells will not express every gene encoded on our DNA but only a specific subset.

An exciting new avenue for our understanding of gene regulation is the importance of the 3D DNA structure. Regulatory regions within our DNA play a major role in regulating gene expression, but arequirement is that the regions come into spatial contact with the associated genes.

It is well known today, that the way the DNA is folded within the cell is tightlyregulated and determines the contact between different regulatory regions with different genes and thereby determines which genes areswitched on or off.

By looking at individual stem cells, the researchers willnow be able to better understandhowthese master cells are able to differentiate into different cell types of our body, which could revolutionize regenerative medicine.

Knowing where all the genes and control elements are at a given moment will help us understand the molecular mechanisms that control and maintain their expression. () Currently, these mechanisms are poorly understood and understanding them may be key to realizingthe potential of stem cells in medicine.says Prof Ernest Laue, who supervised the study.

A better understanding of how the genome structure determines whether genes are switched on or off could also be important to understand what happens in cancer. Abnormal genomes might cause changes in DNA folding and thereby lead to abnormal gene expression.

Changes in gene expression which are not based on the DNA sequence are calledepigenetic modifications. Epigenetics is definitely one of the recent hypes within the cancer field.The folding of DNA is only one aspect of epigenetic gene regulation, while direct modifications of the DNA or DNA-associated proteins provide another. Cancer cells often make use of the epigenetic machinery to change gene regulation and support their survival.

A recent study,for example, unveiled the role of epigenetic changes in driving pancreatic cancer metastasis. By understanding what happens on the gene regulatorylevel, the researchers were able to find a compound, which specifically inhibits these epigenetic changes and therebycancer cell progression.

Epigenetic mechanisms definitely play a key role not only to advance our understanding of stem cell commitment and regenerative medicine, but also in disease areas such as cancer research. You can findthe identified 3D structures of the DNA below.

Images via shutterstock.com /Iaremenko Sergii

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The First 3D DNA Structure could advance Stem Cell Therapies - Labiotech.eu (blog)

March 14, 2017

An international research team, led by scientists at University of California San Diego School of Medicine, has created the first cellular model of anorexia nervosa (AN), reprogramming induced pluripotent stem cells (iPSCs) derived from adolescent females with the eating disorder.

Writing in the March 14th issue of Translational Psychiatry, the scientists said the resulting AN neuronsthe disease in a dishrevealed a novel gene that appears to contribute to AN pathophysiology, buttressing the idea that AN has a strong genetic factor. The proof-of-concept approach, they said, provides a new tool to investigate the elusive and largely unknown molecular and cellular mechanisms underlying the disease.

"Anorexia is a very complicated, multifactorial neurodevelopmental disorder," said Alysson Muotri, PhD, professor in the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. "It has proved to be a very difficult disease to study, let alone treat. We don't actually have good experimental models for eating disorders. In fact, there are no treatments to reverse AN symptoms."

Primarily affecting young female adolescents between ages 15 and 19, AN is characterized by distorted body image and self-imposed food restriction to the point of emaciation or death. It has the highest mortality rate among psychiatric conditions. For females between 15 and 24 years old who suffer from AN, the mortality rate associated with the illness is 12 times higher than the death rate of all other causes of death.

Though often viewed as a non-biological disorder, new research suggests 50 to 75 percent of risk for AN may be heritable; with predisposition driven primarily by genetics and not, as sometimes presumed, by vanity, poor parenting or factors related to specific groups of individuals.

But little is actually known about the molecular, cellular or genetic elements or genesis of AN. In their study, Muotri and colleagues at UC San Diego and in Brazil, Australia and Thailand, took skin cells from four females with AN and four healthy controls, generated iPSCs (stem cells with the ability to become many types of cells) from these cells and induce these iPSCs to become neurons.

(Previously, Muotri and colleagues had created stem cell-derived neuronal models of autism and Williams syndrome, a rare genetic neurological condition.)

Then they performed unbiased comprehensive whole transcriptome and pathway analyses to determine not just which genes were being expressed or activated in AN neurons, but which genes or transcripts (bits of RNA used in cellular messaging) might be associated with causing or advancing the disease process.

No predicted differences in neurotransmitter levels were observed, the researchers said, but they did note disruption in the Tachykinin receptor 1 (TACR1) gene. Tachykinins are neuropeptides or proteins expressed throughout the nervous and immune systems, where they participate in many cellular and physiological processes and have been linked to multiple diseases, including chronic inflammation, cancer, infection and affective and addictive disorders.

The scientists posit that disruption of the tachykinin system may contribute to AN before other phenotypes or observed characteristics become obvious, but said further studies employing larger patient cohorts are necessary.

"But more to the point, this work helps make that possible," said Muotri. "It's a novel technological advance in the field of eating disorders, which impacts millions of people. These findings transform our ability to study how genetic variations alter brain molecular pathways and cellular networks to change risk of ANand perhaps our ability to create new therapies."

Explore further: Stem cell-derived 'mini-brains' reveal potential drug treatment for rare disorder

More information: P D Negraes et al, Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons, Translational Psychiatry (2017). DOI: 10.1038/tp.2017.37

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Excerpt from:
Researchers create model of anorexia nervosa using stem cells - Medical Xpress

Some heritable but unstable genetic mutations that are passed from parent to affected offspring may not be easy to investigate using current human-induced pluripotent stem cell (hiPSC) modeling techniques, according to research conducted at The Icahn School of Medicine at Mount Sinai. The study serves to caution stem cell biologists that certain rare mutations, like the ones described in the study, are difficult to recreate in laboratory-produced stem cells.

Stem cell-based disease modeling involves taking cells from patients, such as skin cells, and introducing genes that reprogram the cells into human-induced pluripotent stem cells (hiPSCs). These master cells are unspecialized, meaning they can be pushed to become any type of mature cell needed for research, such as skin, liver or brain. The hiPSCs are capable of renewing themselves over a long period of time, and this emerging stem cell modeling technique is helping elucidate the genetic and cellular mechanisms of many different disorders.

Our study describes how a complex chromosomal rearrangement genetically passed by a patient with psychosis to her affected son was not well recreated in laboratory-produced stem cells, says Kristen Brennand, PhD, Associate Professor of Genetics and Genomic Sciences, Neuroscience, and Psychiatry at the Icahn School of Medicine, and the studys senior investigator. As stem cell biologists dive into studying brain disorders, we all need to know that this type of rare mutation is very hard to model with induced stem cells.

To investigate the genetic underpinnings of psychosis, the research team used hiPSCs from a mother diagnosed with bipolar disease with psychosis, and her son, diagnosed with schizoaffective disorder. In addition to the normal 46 chromosomes (23 pairs), the cells in mother and son had a very small extra chromosome, less than 1/10th normal size. This microduplication of genes is increasingly being linked to schizophrenia and bipolar disorders, and the extra chromosomal bit, known as a marker (mar) element, falls into the category of abnormally duplicated genes.

For the first time, the Mount Sinai research team tried to make stem cells from adult cells with this type of mar defect. Through the process, they discovered that the mar element was frequently lost during the reprogramming process.

While mar elements in the general population are rare (less than .05 percent in newborn infants), more than 30 percent of individuals with these defects are clinically abnormal, and mar elements are also significantly more likely to be found in patients with developmental delays.

The study found that the mothers cells were mosaic, meaning some cells were normal while others were not, and the hiPSCs the team created accurately replicated that condition: some were normal and some had the extra mar chromosome. But the technique did not work well with the sons cells. While all of his cells should have had the mar element, as with his mother, some of the reprogrammed stem cells did not contain the extra bit of chromosome.

We realized we kept losing the mutation in the stem cells we made, and the inability to recreate cells with mar elements may hamper some neuropsychiatric research, says Dr. Brennand. The bottom line is that it is essential that stem cell biologists look for existing mar elements in the cells they study, in order to check that they are retained in the new stem cells.

Reference:

Tcw, J., Carvalho, C. M., Yuan, B., Gu, S., Altheimer, A. N., Mccarthy, S., . . . Brennand, K. J. (2017). Divergent Levels of Marker Chromosomes in an hiPSC-Based Model of Psychosis. Stem Cell Reports. doi:10.1016/j.stemcr.2017.01.010

This article has been republished frommaterialsprovided by Mount Sinai Hospital. Note: material may have been edited for length and content. For further information, please contact the cited source.

Read more:
Stem Cell-based Modelling can be Difficult for Rare Genetic Variants - Technology Networks