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 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.
Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Parisha P
PP
Shah
Greg
G
Donahue
Gabriel L
GL
Otte
Brian C
BC
Capell
David M
DM
Nelson
Kajia
K
Cao
Varun
V
Aggarwala
Hazel A
HA
Cruickshanks
Taranjit Singh
TS
Rai
Tony
T
McBryan
Brian D
BD
Gregory
Peter D
PD
Adams
Shelley L
SL
Berger
D000375:Aging / Q000235:genetics* / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D034921:Lamin Type B / Q000235:genetics* / Q000378:metabolism*; D008745:Methylation; D011371:Progeria / Q000473:pathology; D017434:Protein Structure, Tertiary
D002843:Chromatin; D006657:Histones; D034921:Lamin Type B
chromatin; gene expression; lamin B1; senescence