Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence
- Mahito Sadaie1,6,7,
- Rafik Salama1,6,
- Thomas Carroll1,
- Kosuke Tomimatsu1,2,
- Tamir Chandra1,8,
- Andrew R.J. Young1,
- Masako Narita1,
- Pedro A. Pérez-Mancera1,
- Dorothy C. Bennett3,
- Heung Chong4,
- Hiroshi Kimura5 and
- Masashi Narita1,9
- 1Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom;
- 2Research Centre for Bioscience and Technology, Tottori University, Tottori 683-8503, Japan;
- 3Biomedical Sciences Research Centre, St. George's, University of London, London SW17 0RE, United Kingdom;
- 4Cellular Pathology, Division of Biomedical Sciences, St. George's, University of London, London SW17 0RE, United Kingdom;
- 5Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
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↵6 These authors contributed equally to this work.
Abstract
Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for Lys9 trimethylation on histone H3 (H3K9me3). LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3-positive heterochromatin, thus promoting SAHF formation, which could be inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genome-wide redistribution: first, through the spatial reorganization of chromatin and, second, through gene repression.
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Footnotes
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↵9 Corresponding author
E-mail masashi.narita{at}cruk.cam.ac.uk
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.217281.113.
- Received March 6, 2013.
- Accepted July 22, 2013.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.