Senescence-associated genes are often lineage-specific genes, which are tightly controlled through the epigenetics mechanism. Lineage- or cell-type-specific genes define cellular functionality (represented by senescence-associated secretory phenotype, SASP). Thus, senescence can be viewed as a gain-of-function phenotype. Indeed, SASP genes can be induced through extensive 3D rewiring of the enhancer-promoter network (Olan et al. Nat Commun 2020).
Senescence is often accompanied by global chromatin reorganisation, represented by senescence-associated heterochromatin foci (SAHFs) (Narita et al. Cell 2003). SAHF-formation is associated with upregulation of HMGA1 (Narita et al. Cell 2006) and loss of Lamin B1 (Sadaie et al. Genes Dev 2013). During SAHF-formation, chromatin is organised into concentric epigenetic layers with H3K9m3-core with H3K27me-shell, excluding euchromatin regions (Chandra et al. Mol Cell 2012).
Thus, we suspect that the process is important not only for heterochromatin formation but also for separating active regions from the repressive environment. This notion is supported by our recent data, desilencing of ‘lineage-inappropriate’ genes from H3K9me3 heterochromatin primarily at peri-SAHF regions (Tomimatsu et al. Nat Aging 2022).
We are asking to what extent we can generalise the SAHF-like organisation and its impact on gene regulation. See our recent review article on this topic (Olan and Narita. Annu. Rev. Cell Dev. Biol. 2022)