Cells can promote tumor suppression via a process of irreversible arrest of proliferation called senescence. This process is thought to be associated with normal aging, but is also a protective measure against run-away cell replication. Studying the basic science of senescence gives biomedical researchers a better understanding of the mechanisms behind age-related diseases such as cancer.
Scientists from the Perelman School of Medicineat the University of Pennsylvania involved in Epigenetice, the science of how gene activity can be altered without actual changes in DNA sequence, have found that epigenetic factors play a role in senescence.
Lamin B1 down-regulation in senescence is a key trigger of global and local chromatin changes that affect gene expression, aging, and cancer.
Epigenetic factors act on the structures in which genes reside, called chromatin. The scientists found that senescent cells appear to undergo changes in their chromatin. They also found similar changes in cells that are prematurely aging. These changes take place inside the chromatin of a cell?s nucleus. In the chromatin, DNA is wound around proteins called histones. Enzymes called histone modifiers mark the chromatin ? like using sticky notes as reminders ? to open up or close down regions of the genome, which makes these areas more or less available to be read as a gene.
The scientists, including Shelley Berger, PhD, professor of Cell and Developmental Biology at the Perelman School of Medicineat the University of Pennsylvania and Parisha Shah, PhD, a postdoctoral fellow in the Berger lab, compared differences in the presence of the genome-wide sticky notes between two lung cell populations, one at the start of proliferation, as a control, and the other at the end of its replication cycle and senescent. Their study, which also included scientists from theInstitute of Cancer Sciences, University of Glasgow, UK and the Department of Biology, Penn Genome Frontiers Institute, was, in part, supported by the National Institute on Agingand the Ellison Medical Foundation.
Lamin B1
The researchers found that when a nuclear protein called lamin B1 is deleted in senescent cells, large-scale changes in gene expression, and likely chromatin, occurred. The team surmised that the loss of lamin B1 causes changes in the architecture of chromatin and this adds to the aging of cells. The study results were published in the July 19, 2013 online edition of Genes & Development.[1]
?Senescence is really a balancing act between aging and cancer,? noted Berger, who is also a director of the Penn Epigenetics Program. ?While chromatin regulation and down-regulation of lamin B1 have been known to be altered during senescence, how the two processes interact has been poorly understood.?
Inside the cell
Lamin B1 is part of the lamina, a network lining the inside of the membrane of the nucleus. It provides support to keep 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 the case of silencing genes, the proteins of the lamina do this by creating tight connections between parts of the chromatin and the nuclear membrane.
Changes in chromatin signature
The scientists compared genome-wide Lys4 trimethylation on histone H3 (H3K4me3) and H3K27me3 distributions between proliferating and senescent human cells and found dramatic differences in senescence, including large-scale domains of H3K4me3- and H3K27me3-enriched mesas and H3K27me3-depleted canyons.
The scientists were 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. They noticed that nearly 30% 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 modifications – the molecular sticky notes ? the scientists found remarkable differences in the senescent cells. These differences included large-scale domains of sticky-note-enriched histone mesas and sticky-note-depleted histone canyons, as graphically depicted when comparing the gains and losses. The enriched mesas form at lamin B1-associated domains (LADs) on the chromatin. In addition, they found that intentional lamin B1 reduction in proliferating cell populations also triggers premature senescence and, importantly, leads to chromatin mesas and canyons in the cells.
Hutchinson-Gilford progeria syndrome
Fibroblast cells from patients with Hutchinson-Gilford progeria syndrome, a genetic condition characterized by dramatic and rapid aging beginning in childhood caused by a related mutated lamin A protein, also showed the enriched marker mesas. The researchers concluded that this suggested a link between premature chromatin changes and accelerated cell senescence. Other researchers have found that progeria symptoms are delayed in a mouse model of the human syndrome when the mice are engineered to clear all senescent cells via apoptosis, or programmed cell death.
Comparing cells from children with progeria and their symptom-free parents, the researchers found that the progeria cells have increased chromatin sticky note mesas in lamin regions that are not normally marked as mesas. These areas of the genome are called permissive chromatin. This so-called leniency is the signature of an aging cell. The parents? control cells do not have this permissive chromatin compared to their children?s.
Chromatin reorganization
Looking at the results, Shah, noted: “Our data illustrate profound chromatin reorganization during senescence and suggest that lamin B1 down-regulation in senescence is a key trigger of global and local chromatin changes that affect gene expression, aging, and cancer.?
“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,” Berger said.
?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,? Berger added.
For more information:
[1] Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K, Aggarwala V, et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape.Genes Dev. 2013 Aug 15;27(16):1787-99. doi
: 10.1101/gad.223834.113. Epub 2013 Aug 9. [Article][PubMed]
Illustration Courtesy:Parisha Shah, PhD; Shelley Berger, PhD, Perelman School of Medicine, University of Pennsylvania; Genes & Development. Click here to enlarge the illustrations.
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