Public release date: 26-Sep-2013 [ | E-mail | Share ]

Contact: Graham Shaw graham.shaw@icr.ac.uk 44-020-715-35380 Institute of Cancer Research

Scientists have used a brand new technique for examining individual stem cells to uncover dramatic differences in the gene expression levels which genes are turned 'up' or 'down' between apparently identical 'sister' pairs.

The research, published today (Thursday) in Stem Cell Reports, was conducted and funded by The Institute of Cancer Research, London. It provides the latest evidence that despite having identical DNA, sister stem cells can display considerable differences in their molecular characteristics.

The study showed that DNA methylation, a process that controls which genes are expressed in cells, plays an important role in generating non-genetic (or 'epigenetic') differences between sister cells.

DNA methylation could therefore be one of the reasons for the major molecular variation between different cancer cells in the same tumour and drugs to reduce methylation might help control variation and make cancers easier to treat.

In the new research, scientists at The Institute of Cancer Research (ICR) developed a novel micro-dissection technique to separate pairs of sister embryonic stem cells for single cell RNA analysis [1].

Using their new high-tech method, researchers separated and isolated mouse stem cells from their sister pairs and measured the behaviour of key genes known to be expressed in those cells. By comparing which of these genes were up or down regulated, they determined the levels of similarity between sister cells at the molecular level for the first time.

They found that under normal conditions, pairs of sister stem cells displayed considerable differences to each other, showing nearly as much diversity as two cells from different sister pairs.

The researchers then looked at cells grown in the presence of a chemical cocktail called 2i, which reverts cells back to their most primitive stem cell state where they can make identical copies of themselves. They found that the cells had reduced levels of two enzymes critical for DNA methylation and they produced more similar sister cells.

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Study of 'sister' stem cells uncovers new cancer clue

Javascript is currently disabled in your web browser. For full site functionality, it is necessary to enable Javascript. In order to enable it, please see these instructions. 12 hours ago Binding of the signaling protein ERK2 helps human embryonic stem cells to self-renew and proliferate. Credit: 2013 Clay Glennon, University of WisconsinMadison

Human embryonic stem cells (hESCs) retain the ability to form any cell type in the body. They do this thanks to the interplay of many proteins, including one involved in cell signaling known as extracellular signal-regulated kinase 2, or ERK2. By detailing all the sites in the genome where ERK2 binds, a team led by A*STAR scientists has now mapped the regulatory network by which this enzyme keeps hESCs in a state of self-renewing pluripotency.

"ERK2 appears to be involved in active transcription of a large number of genes in hESCs," says senior study author Huck-Hui Ng, executive director of the A*STAR Genome Institute of Singapore. "This is a first whole-genome map to describe the kinase-chromatin interactions in human stem cells" he adds.

Ng and his collaboratorswho included researchers from A*STAR, the National University of Singapore and the Max Planck Institute for Molecular Genetics in Berlin, Germanyused a technique for unraveling interactions between proteins and DNA called ChIP-seq to pinpoint some 12,000 sites where ERK2 binds to chromosomes in hESCs. They found that close to two-thirds of these ERK2 binding sites occurred near so-called 'promoter' regions of DNA that initiate transcription of particular genes. They also showed that these promoters activate an assortment of genes variously involved in metabolic pathways and cell cycle progression, including those essential for the survival, proliferation and pluripotency of the cells (see image).

The researchers then looked for transcription factors that ERK2 might interact with to activate these genes. Based on the type of DNA motifs found at ERK2 binding sites, they identified four candidate interaction partners. Silencing three of these candidates had no effect on hESC identity, but depleting a transcription factor called ELK1 led to the loss of pluripotency in the cells, the researchers noted.

Ng's team showed that ELK1 has a dual function. It works with ERK2 to activate the expression of metabolism-related genes. Yet, in the absence of ERK2, ELK1 can also repress genes involved in differentiation and lineage-commitment. "The balance between active gene expression and repression of differentiation genes is characteristic for the capacity of embryonic stem cells to become more specialized cells," explains Jonathan Gke, a postdoctoral fellow in Ng's lab and the first author of the study.

"The dual role of ELK1 indicates that a change in activation most likely will affect repression as well, and vice versa," Gke adds. "Therefore, activation and repression are to some degree two sides of the same coin."

Explore further: Scientists discover molecular communication network in human stem cells

More information: Gke, J., et al. Genome-wide kinase-chromatin interactions reveal the regulatory network of ERK signaling in human embryonic stem cells, Molecular Cell 50, 844855 (2013). dx.doi.org/10.1016/j.molcel.2013.04.030

Scientists at A*STAR's Genome Institute of Singapore (GIS) and the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin (Germany) have discovered a molecular network in human embryonic stem cells (hESCs) that integrates ...

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Location map for signaling protein identifies key molecular targets in human embryonic stem cells

Maggie Alejos arrived here in June from St. Anne, Ill., with her husband, her daughter and a cashiers check for $13,500, payable to the Regenerative Medicine Institute.Rail-thin, with an oxygen tube anchored above her upper lip, Alejos, a retired Army nurse, has coped with emphysema for a dozen of her 65 years.

Once she came close enough to a lung transplant that doctors prepared her for surgery, only to discover that the donor lung was unfit. At a hospital here, doctors affiliated with the institute extracted about seven ounces of fat from her thighs, hoping to harvest about 130 million stem cells and implant them in her failing lungs.

Across the Internet where Alejos learned about the Tijuana institute adult stem cells are promoted as a cure for everything from sagging skin to severed spinal cords.

On the surface, the claim is plausible. Scientists have discovered that fat, bone marrow and other parts of the body contain stem cells, immature cells that can rejuvenate themselves, at least in the tissue they are naturally found.

But it has yet to be proved that these cells can regenerate no matter where they are placed, or under what conditions this might occur. Moreover, questions about safety remain unanswered.

These sober realities do not appear to have slowed the rise of an international industry catering to customers who may pay tens of thousands of dollars in cash for their shot at a personal miracle. (Some foreign operators offer creative variations on the theme, like cells from sharks and sheep.)

Domestic providers, too, can push the limits. In July, for example, a former pathologist at the Medical University of South Carolina pleaded guilty to illegally processing and shipping stem cells for treatment without approval from the university or the Food and Drug Administration.

The number of clinics and products has reached the point that scientists fear repercussions for their own work. Dr. Hesham Sadek of the University of Texas Southwestern Medical Center in Dallas, who is studying heart muscle regeneration, worries that the marketing deluge now makes it hard for patients to tell science from swindle, and all that lies on the spectrum in between.

It really has the potential to undermine the legitimacy of the whole field, he said.

Even though Tijuana has perhaps 20 clinics offering adult stem cell therapy, Dr. Javier Lopez, founder of the Regenerative Medicine Institute, says it is his that has become the poster company to knock down.

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For a miracle, more turn to stem cells