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

Kosuke Tomimatsu, Dóra Bihary, Ioana Olan, Aled J. Parry, Stefan Schoenfelder, Adelyne S.L. Chan, Guy St C. Slater, Yoko Ito, Peter J. Rugg-Gunn, Kristina Kirschner, Camino Bermejo-Rodriguez, Tomomi Seko, Hiroyuki Kugoh, Ken Shiraishi, Koji Sayama, Hiroshi Kimura, Peter Fraser, Masako Narita, Shamith A. Samarajiwa, Masashi Narita

    Research output: Contribution to journalArticlepeer-review

    7 Citations (Scopus)


    Senescence is a fate-determined state, accompanied by reorganization of heterochromatin. Although lineage-appropriate genes can be temporarily repressed through facultative heterochromatin, stable silencing of lineage-inappropriate genes often involves the constitutive heterochromatic mark, histone H3 lysine 9 trimethylation (H3K9me3). The fate of these heterochromatic genes during senescence is unclear. In the present study, we show that a small number of lineage-inappropriate genes, exemplified by the LCE2 skin genes, are derepressed during senescence from H3K9me3 regions in fibroblasts. DNA FISH experiments reveal that these gene loci, which are condensed at the nuclear periphery in proliferative cells, are decompacted during senescence. Decompaction of the locus is not sufficient for LCE2 expression, which requires p53 and C/EBPβ signaling. NLRP3, which is predominantly expressed in macrophages from an open topologically associated domain (TAD), is also derepressed in senescent fibroblasts due to the local disruption of the H3K9me3-rich TAD that contains it. NLRP3 has been implicated in the amplification of inflammatory cytokine signaling in senescence and aging, highlighting the functional relevance of gene induction from ‘permissive’ H3K9me3 regions in senescent cells.

    Original languageEnglish
    Pages (from-to)31-45
    Number of pages15
    JournalNature Aging
    Issue number1
    Publication statusPublished - Jan 2022

    All Science Journal Classification (ASJC) codes

    • Geriatrics and Gerontology
    • Ageing
    • Neuroscience (miscellaneous)


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