Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape

Parisha P. Shah, Greg Donahue, Gabriel L. Otte, Brian C. Capell, David M. Nelson, Kajia Cao, Varun Aggarwala, Hazel A. Cruickshanks, Taranjit Singh Rai, Tony McBryan, Brian D. Gregory, Peter D. Adams, Shelley L. Berger

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

Senescence is a stable proliferation arrest, associated with an altered secretory pathway, thought to promote tumor suppression and tissue aging. While chromatin regulation and lamin B1 down-regulation have been implicated as senescence effectors, functional interactions between them are poorly understood. We compared genome-wide Lys4 trimethylation on histone H3 (H3K4me3) and H3K27me3 distributions between proliferating and senescent human cells and found dramatic differences in senescence, including large-scale domains of H3K4me3- and H3K27me3-enriched "mesas" and H3K27me3-depleted "canyons." Mesas form at lamin B1-associated domains (LADs) in replicative senescence and oncogene-induced senescence and overlap DNA hypomethylation regions in cancer, suggesting that pre-malignant senescent chromatin changes foreshadow epigenetic cancer changes. Hutchinson-Gilford progeria syndrome fibroblasts (mutant lamin A) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence. Canyons mostly form between LADs and are enriched in genes and enhancers. H3K27me3 loss is correlated with up-regulation of key senescence genes, indicating a link between global chromatin changes and local gene expression regulation. Lamin B1 reduction in proliferating cells triggers senescence and formation of mesas and canyons. Our data illustrate profound chromatin reorganization during senescence and suggest that lamin B1 down-regulation in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging, and cancer.

LanguageEnglish
Pages1787-1799
Number of pages13
JournalGenes and Development
Volume27
Issue number16
DOIs
Publication statusPublished - 15 Aug 2013

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Chromatin
Gene Expression
Cell Aging
Neoplasms
Down-Regulation
Progeria
Lamin Type A
Secretory Pathway
Gene Expression Regulation
lamin B1
Oncogenes
Epigenomics
Histones
Genes
Up-Regulation
Fibroblasts
Genome
DNA

Keywords

  • Chromatin
  • Gene expression
  • Lamin B1
  • Senescence

Cite this

Shah, P. P., Donahue, G., Otte, G. L., Capell, B. C., Nelson, D. M., Cao, K., ... Berger, S. L. (2013). Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes and Development, 27(16), 1787-1799. https://doi.org/10.1101/gad.223834.113
Shah, Parisha P. ; Donahue, Greg ; Otte, Gabriel L. ; Capell, Brian C. ; Nelson, David M. ; Cao, Kajia ; Aggarwala, Varun ; Cruickshanks, Hazel A. ; Rai, Taranjit Singh ; McBryan, Tony ; Gregory, Brian D. ; Adams, Peter D. ; Berger, Shelley L. / Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. In: Genes and Development. 2013 ; Vol. 27, No. 16. pp. 1787-1799.
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Shah, PP, Donahue, G, Otte, GL, Capell, BC, Nelson, DM, Cao, K, Aggarwala, V, Cruickshanks, HA, Rai, TS, McBryan, T, Gregory, BD, Adams, PD & Berger, SL 2013, 'Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape', Genes and Development, vol. 27, no. 16, pp. 1787-1799. https://doi.org/10.1101/gad.223834.113

Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. / Shah, Parisha P.; Donahue, Greg; Otte, Gabriel L.; Capell, Brian C.; Nelson, David M.; Cao, Kajia; Aggarwala, Varun; Cruickshanks, Hazel A.; Rai, Taranjit Singh; McBryan, Tony; Gregory, Brian D.; Adams, Peter D.; Berger, Shelley L.

In: Genes and Development, Vol. 27, No. 16, 15.08.2013, p. 1787-1799.

Research output: Contribution to journalArticle

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AU - Shah, Parisha P.

AU - Donahue, Greg

AU - Otte, Gabriel L.

AU - Capell, Brian C.

AU - Nelson, David M.

AU - Cao, Kajia

AU - Aggarwala, Varun

AU - Cruickshanks, Hazel A.

AU - Rai, Taranjit Singh

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AU - Gregory, Brian D.

AU - Adams, Peter D.

AU - Berger, Shelley L.

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