Epigenetic Basis of Cellular Senescence and Its Implications in Aging
Nacarelli T, Liu P, Zhang R. Epigenetic Basis of Cellular Senescence and Its Implications in Aging. Genes (Basel). 2017 Nov 24;8(12):343. doi: 10.3390/genes8120343. PMID: 29186801; PMCID: PMC5748661.
Cellular senescence serves an important tumour supressive role and prevents stressed cells from turning oncogenic and proliferating.
However, long-term or chronic senescence has deleterious effects. Their cell-autonomous proliferative arrest is maintained by p53 and CDK4 and CDK6 inhibitor p16. p53 upregulates p21 to arrest the cell cycle. p16 is activated by stress-related pathways like the p38 MAP kinase pathway. Since senescence cells resist death and can persist, they may accumulate and exhaust tissues of proliferation-competent cells and renewable stem cells, overall reducing the its regenerative capacity. The SASP can also promote DNA damage response and proliferative arrest and promote senescence in neighbouring cells.
Epigenetic changes during senescence and ageing
Senescence-associated heterochromatic foci form during cellular senescence and are enriched in markers that repress proliferation-related genes. SAHF may not always be found in senescent cells. The heterochromatin in the SAHF is formed through heterochromatin redistribution from its loss from nuclear periphery, which is mediated by a loss of lamin B1. Lamin B1 is downregulated in senescence and silencing it can induce senescence.
Epigenetic effectors of cellular senescence
High Mobility Group proteins HMGA1 and HMGA2 accumulate in the chromatin of senescent cells, displacing linker histone H1, and structurally support the SAHF. HMGB1 has p53-dependent secretion and activates NFκB and pro-inflammatory pathways. HMGA2 also has pro-inflammatory roles, different from HMGB1, one of which is binding the loci of SASP genes to prevent them from being incorporated into SAHF regions that repress transcription - the SASP could be separated from the more beneficial senescent cell cycle arrests.
Epigenetic regulators of the SASP
Inhibition of the SASP enhancer BRD4 suppressed the SASP while maintaining the arrest of senescent cells. SASP is negatively regulated by SIRT1. With SIRT1 knockdown or reduced expression in senescence, acetylation of H3K9 and H4K16 is increased at interleukin 6 and 8 promoters and their increased transcription.