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.
This study was supported by funding from a New York State Stem Cell Science Award (C024285) and a National Institutes of Health Grant (R01CA154683).
About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai. Established in 1968, the Icahn School of Medicine is one of the leading medical schools in the United States, and is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2012, U.S. News & World Report ranked The Mount Sinai Hospital 14th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and by U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.
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Journal
Nature Communications