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

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 unde...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759695/
https://www.ncbi.nlm.nih.gov/pubmed/23934658
http://dx.doi.org/10.1101/gad.223834.113
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author 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.
author_facet 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.
author_sort Shah, Parisha P.
collection PubMed
description 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.
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spelling pubmed-37596952014-02-15 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. Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2013-08-15 /pmc/articles/PMC3759695/ /pubmed/23934658 http://dx.doi.org/10.1101/gad.223834.113 Text en © 2013, Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
spellingShingle Research Paper
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
title Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape
title_full Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape
title_fullStr Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape
title_full_unstemmed Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape
title_short Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape
title_sort lamin b1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759695/
https://www.ncbi.nlm.nih.gov/pubmed/23934658
http://dx.doi.org/10.1101/gad.223834.113
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