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

Tomimatsu, K. et al. (2022) Locus-specific induction of gene expression from heterochromatin loci during cellular senescence. Nature Aging, 2, pp. 31-45. (doi: 10.1038/s43587-021-00147-y)

Abstract

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.

• Item Type: Articles
• Additional Information: This work is supported by a Cancer Research UK Cambridge Institute core grant (no. C9545/A29580) to Masashi N.’s laboratory, and in part by the Human Frontier Science Program (no. RGY0078/2010) (to Masashi N.). Masashi N. is also supported by the Medical Research Council (MRC) (MR/M013049/1 and MR/R010013/1), BBSRC (BB/S013466/1) and Diabetes UK via BIRAX and the British Council (65BX18MNIB). I.O. is supported by the Cancer Research UK Pioneer grant (no. C63389/A30462). S.A.S and D.B. are supported by the MRC (MC_UU_12022/10). S.S. is supported by the UKRI Biotechnology and Biological Science Research Council (BB/J004480/1), the UKRI MRC (MR/T016787/1) and a Career Progression Fellowship from the Babraham Institute. P.J.R.-G. is supported by the BBSRC (BBS/E/B/000C0422), the MRC (MR/T011769/1 and MR/N018419/1) and the Wellcome Trust (215116/Z/18/Z). H.K. is supported by JSPS KAKENHI (nos. JP17H01417 and JP18H05527).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kirschner, Dr Kristina
• Authors: Tomimatsu, K., Bihary, D., Olan, I., Parry, A. J., Schoenfelder, S., Chan, A. S. L., Slater, G. S. C., Ito, Y., Rugg-Gunn, P. J., Kirschner, K., Bermejo-Rodriguez, C., Seko, T., Kugoh, H., Shiraishi, K., Sayama, K., Kimura, H., Fraser, P., Narita, M., Samarajiwa, S. A., and Narita, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Aging
• Publisher: Nature Research
• ISSN: 2662-8465
• ISSN (Online): 2662-8465
• Published Online: 23 December 2021
• Copyright Holders: Copyright © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
• First Published: First published in Nature Aging 2: 31-45
• Publisher Policy: Reproduced in accordance with the publisher copyright policy