title: Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence.
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.
authors: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
authors: Mahito
authors: M
authors: Sadaie
authors: Rafik
authors: R
authors: Salama
authors: Thomas
authors: T
authors: Carroll
authors: Kosuke
authors: K
authors: Tomimatsu
authors: Tamir
authors: T
authors: Chandra
authors: Andrew R J
authors: AR
authors: Young
authors: Masako
authors: M
authors: Narita
authors: Pedro A
authors: PA
authors: Pérez-Mancera
authors: Dorothy C
authors: DC
authors: Bennett
authors: Heung
authors: H
authors: Chong
authors: Hiroshi
authors: H
authors: Kimura
authors: Masashi
authors: M
authors: Narita
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D005786:Gene Expression Regulation; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D006570:Heterochromatin; D006657:Histones; D034921:Lamin Type B
keywords: Lamin B1; epigenetics; senescence
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