Stem Cell Depletion by Global Disorganization of the H3K9me3 Epigenetic Marker in Aging.

Abstract

Epigenomic change and stem cell exhaustion are two of the hallmarks of aging. Accumulation of molecular damage is thought to underlie aging, but the precise molecular composition of the damage remains controversial. That some aging phenotypes, especially those that result from impaired stem cell function, are reversible suggest that such "damage" is repairable. Evidence is accumulating that dysfunction in aging stem cells results from increasing, albeit, subtle disorganization of the epigenome over time. Zhang et al. (2015) report that decreasing levels of WRN, Werner's syndrome (WS) helicase, with increasing age results in loss of heterochromatin marks in mesenchymal stem cells (MSCs) and correlates with an increased rate of cellular senescence. Although WRN plays a role in DNA repair, WRN exerted its effects on aging via maintaining heterochromatin, evidenced by reduced levels of interacting chromatin regulators heterochromatin protein 1α (HP1α), suppressor of variegation 3-9 homolog 1 (SUV39H1), and lamina-associated polypeptide 2β (LAP2β) as well as modified histone H3K9me3. Reducing expression of chromatin modeling co-factors SUV39H1 or HP1α in wild-type MSCs recapitulates the phenotype of WRN deficiency, resulting in reduced H3K9me3 levels and increased senescence without induction of markers of DNA damage, suggesting that chromatin disorganization and not DNA damage is responsible for the pathology of WS during aging in animals. Ectopic expression of HP1α restored H3K9me3 levels and repressed senescence in WRN-deficient MSCs. That HP1α can also suppress senescence in Hutchinson-Gilford progeria syndrome (HGPS) and extend life span in flies when over-expressed suggests that HP1α and H3K9me3 play conserved roles in maintenance of cell state. H3K9me3 levels are dynamic and expected to be potentially responsive to manipulation by extrinsic factors. Recent reports that migration inhibitory factor (MIF) or periodic fasting rejuvenate old MSCs provide the opportunity to link intrinsic and extrinsic mechanisms of aging in novel and potentially medically important ways and may lead to anti-aging treatments that reorganize the epigenome to rejuvenate cells and tissues.