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Penn study links epigenetics, aging, and mutations in nuclear proteins to create a better understanding of cancer and rare disorders.
Senescence is the state or process of ageing. Cellular senescence is a phenomenon where isolated cells demonstrate a limited ability to divide in culture.
The lamina, a network of proteins lining the inside of the membrane of the nucleus, provides support to the shape of the nucleus. It also regulates DNA replication by making some areas of the genome less restricted or more available (permissive) to be translated into proteins. In the case of silencing (turning off) genes, the proteins of the lamina do so by tightening connections between parts of the chromatin and the nuclear membrane, thererby restricing the unraveling of histone proteins.
Researchers from the Perelman School of Medicine at the University of Pennsylvania have found that epigenetic factors play a role in senescence by acting on the chromatin structures in which genes reside. Senescent cells appear to undergo changes in their chromatin similar to changes in cells that are prematurely aging.
These changes take place deep inside the nucleus where DNA winds around proteins called histones. Histone enzymes mark the chromatin – much like sticky notes mark book chapters – to open up or close down regions of a gene. Opening up a gene makes it more available to be “read” or "expressed." Epigenetics is the science of how gene activity can be altered by such chemistry without actually changing the sequence of the DNA molecule.
Shelley Berger, PhD, professor of Cell and Developmental Biology and director of the Penn Epigenetics Program, plus Parisha Shah, PhD, a postdoctoral fellow in the Berger lab, and colleagues, compared differences in the presence of the genome-wide sticky notes (histones) that exist between two lung cell populations, one at the start of proliferation—as a control—and the other at the end of its replication cycle—at senescence.
They found that when a nuclear protein called lamin B1 is deleted in senescent cells, large-scale changes occur in gene expression, and likely in chromatin structure. The team surmised that the loss of lamin B1 caused the changes in the architecture of chromatin that adds to the aging of cells. They report their findings in Genes & Development.
Lamin B1 is part of the lamina, a network lining the inside of the membrane of the nucleus. It provides support to the shape of the nucleus and also regulates DNA replication by making some areas of the genome less or more available to be translated into proteins. In order to silence genes, the proteins of the lamina create tight connections between parts of the chromatin and the nuclear membrane.
The Penn team was surprised by the large portion of the genome that changed its chromatin signature in senescence, particularly in the tightly bound laminar regions in the senescent cell population. In fact, nearly 30 percent of the human genome, as measured by changes in the actual sequence of nucleic acid bases, was different between the two cell populations
When comparing gains and losses of two histone modifiers—those molecular sticky notes—the team found remarkable differences in the senescent cells. Differences including large-scale domains of “sticky-note”-enriched histone “mesas” and “sticky-note”-depleted histone “canyons,” graphically reflected in comparisons of histone gains and losses.
Enriched histone “mesas” form at lamin B1-associated areas on chromatin. Additionally, reduction of lamin B1 in proliferating cell populations triggers premature senescence and reflects as chromatin “canyons.”
Comparing cells from children with progeria and their symptom-free parents, the team found that progeria cells have increased chromatin “sticky note” mesas in lamina regions not normally marked as mesas. These areas of the genome are called “permissive” chromatin, and are the signature of an aging cell. Progeria parents’ control cells do not have this permissive chromatin areas as compared to their children’s genes.
Shah, the first author on this study, concludes that “our data illustrate profound chromatin reorganization during senescence and suggest that lamin B1 downregulation in senescence is a key trigger of global and local chromatin changes that affect gene expression, aging, and cancer.”
Berger adds that “once we know the chromatin changes that occur during normal aging, then we can compare and study aberrant chromatin alterations that occur in abnormal aging, including human brain degeneration, which is a growing problem in the aging human population.
“What’s more, since many human diseases exponentially increase with age – one obvious example is cancer – the goal of these studies is to provide insight into the relationship between age and mechanisms of age-related disease” says Berger.
Co-authors are also from the Institute of Cancer Sciences, University of Glasgow, UK and the Department of Biology, Penn Genome Frontiers Institute.
This work was supported in part by the National Institute on Aging (P01AG031862) and the Ellison Medical Foundation.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.
Original press release:http://www.uphs.upenn.edu/news/News_Releases/2013/08/berger/