Researchers from the Icahn School of Medicine at Mount Sinai have discovered that a particular protein prevents normal cells from being reprogrammed into cells that resemble stem cells, providing new insight into how they may lose their plasticity during normal development. This finding has broad-reaching implications for how cells change during both normal and disease development. The data are published this week in Nature Communications.
In a previous study, Emily Bernstein, PhD, and her team at Mount Sinai studied the natural progression of melanoma using mouse and human cells, as well as patient samples, and found that the loss of a specific histone variant called macroH2A, which is a protein that helps package DNA, was directly related to the growth and metastasis of melanoma. In the current study, her team wanted to find out how this molecule might act as a barrier to cellular reprogramming. The importance of cellular reprogramming has been recently highlighted by the winners of the Nobel Prize of Medicine (2012), and explores the capacity of reversing adult cells to an early stage of development, the so called embryonic stem cell.
Working with researchers at the University of Pennsylvania, Dr. Bernstein evaluated mice that were genetically engineered to lack macroH2A in comparison to control or "wild-type" mice. They used skin cells from these mice and attempted to reprogram the cells in petri dishes into pluripotent cells. They found that the cells derived from mice without macroH2A were much more plastic, meaning they were more easily reprogrammed into stem-like cells, compared to the wild-type mice. This indicates that macroH2A may block cellular reprogramming by silencing genes required for plasticity.
"This is the first evidence of the involvement of a histone variant protein as an epigenetic barrier to induced pluripotency (iPS) reprogramming," said Dr. Bernstein, who is an Assistant Professor of Oncological Sciences and Dermatology at the Graduate School of Biomedical Sciences at Mount Sinai, and corresponding author of the study. "These findings help us to understand the progression of different cancers and how macroH2A might be acting as a barrier to tumor development."
Next, Dr. Bernstein and her team plan to create cancer cells in a petri dish by manipulating healthy cells with genetic mutations often associated with cancer, coupled to removal of macroH2A to examine whether the cells are capable of forming tumors.
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