Locus-specific induction of gene expression from heterochromatin loci during cellular senescence

Abstract

Cellular senescence is a fate-determined state, accompanied by reorganization of heterochromatin. While lineage-appropriate genes can be temporarily repressed through facultative heterochromatin, stable silencing of lineage-inappropriate genes often involves the constitutive heterochromatic mark, histone H3K9me3. The fate of these heterochromatic genes during the chromatin reorganization accompanying senescence is unclear. Here we show a small number of lineage-inappropriate genes are derepressed in senescent cells from H3K9me3 regions that gain open chromatin marks. DNA FISH experiments reveal that these gene loci, which are tightly condensed at the nuclear periphery in proliferative cells, are physically decompacted during senescence. Among these gene loci, NLRP3 is predominantly expressed in immune cells, such as macrophages, where it resides within an open topologically associated domain (TAD). In contrast, NLRP3 is derepressed in senescent fibroblasts, potentially due to the local disruption of the H3K9me3-rich TAD that contains it. The role of NLRP3 has been implicated in the amplification of inflammatory cytokine signalling in senescence and aging, underscoring the functional relevance of gene induction from ‘permissive’ H3K9me3 regions in senescent cells.

Mitochondria and sensory processing in inflammatory and neuropathic pain

“…NLRP3 inflammasome activation has been linked to amplified inflammatory cytokine signaling in senescent cells (259,260). The expression of NLRP3 inflammasome related molecules (NLRP3, ASC, caspase-1, IL-1β, IL-18) is increased in the synovial tissue of collagen-induced arthritis (CIA) mice (88,192,261) and MIA-induced OA rats (89,90).…”

p53 in senescence – it's a marathon, not a sprint

“…Thus, these genes are regulated during epidermal differentiation in a spatiotemporal manner through a timely reduction of facultative heterochromatin activity (marked by histone H3K27me3) [55]. These genes have such a specialised function that they are tightly silenced in other cell types, such as fibroblasts, where the EDC is enriched for histone H3K9me3 (a marker of constitutive heterochromatin) and heavily compacted at the nuclear periphery, exemplifying a stable silencing mechanism of ‘lineage‐inappropriate genes’ [56]. However, our recent study revealed that, in fibroblasts, genes within this locus, most notably Late cornified envelope 2 ( LCE2 ) genes, are ectopically de‐silenced during senescence but not upon acute DNA damage treatment nor E1A/RAS‐transformation, in a p53‐dependent manner [56].…”

“…These genes have such a specialised function that they are tightly silenced in other cell types, such as fibroblasts, where the EDC is enriched for histone H3K9me3 (a marker of constitutive heterochromatin) and heavily compacted at the nuclear periphery, exemplifying a stable silencing mechanism of ‘lineage‐inappropriate genes’ [56]. However, our recent study revealed that, in fibroblasts, genes within this locus, most notably Late cornified envelope 2 ( LCE2 ) genes, are ectopically de‐silenced during senescence but not upon acute DNA damage treatment nor E1A/RAS‐transformation, in a p53‐dependent manner [56]. Surprisingly, the LCE2 genes are induced without apparent loss of the H3K9me3 mark, but rather through physical decompaction of the locus.…”

“…Indeed, p53 and a SASP‐driving TF, C/EBPβ, are both required for most LCE2 genes during senescence, where double knockdown of these TFs results in a more robust inhibition of LCE2 induction than single knockdown. Moreover, C/EBPβ ChIP‐seq uncovered its binding at multiple LCE2 promoters [56]. This potentially highlights an additional layer of crosstalk between p53 and the SASP.…”

“…This potentially highlights an additional layer of crosstalk between p53 and the SASP. Interestingly, in a transcriptomic dataset derived from a mouse arthritis model [58], synovial fibroblasts in the chronic phase appear to express higher levels of senescence markers (including Cdkn1a , encoding p21), SASP‐related cytokines, and some EDC genes compared to in an acute phase [56]. Although the direct involvement of p53 and the epigenetic conditions in those synovial fibroblasts derived from arthritis tissues need to be validated, the data support a link between p53‐mediated lineage inappropriate gene expression and senescence in vivo .…”