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Genome-wide mapping of H4K20me3 in proliferating and senescent IMR90 cells.

ABSTRACT: Cellular senescence is a stable proliferation arrest and tumor suppressor mechanism. Abundance of histone modification, H4K20me3, has been reported to increase in senescent cells. Generally, H4K20me3 promotes formation of compacted transcriptionally silent constitutive heterochromatin, but its specific role in senescence is unknown. Here, we show that in senescent cells H4K20me3 is enriched at specific families of gene repeats (ZNFs, Olfactory Receptors, Protocadherins), and DNA sequences contained within senescence-associated heterochromatin (senescence-associated heterochromatin (SAHF)). Furthermore, in senescent cells, but not proliferating cells, H4K20me3 is also markedly enriched at bodies of repressed genes, including proliferation-promoting genes. Ectopic expression of SUV420H2, responsible for deposition of H4K20me3, reinforces senescence-associated proliferation arrest, and slows proliferation of transformed cells and tumorigenesis in vivo. These results indicate a dedicated role for H4K20me3 in control of nuclear organization and gene expression in senescent cells and stable senescence-associated proliferation arrest and tumor suppression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE59316 | GEO | 2016/05/27

SECONDARY ACCESSION(S): PRJNA255048

REPOSITORIES: GEO

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Project description:Cellular senescence is a stable proliferation arrest in response to stress, associated with an altered secretory pathway (Senescence Associated Secretory Phenotype (SASP)). Senescence-associated proliferation arrest and the SASP are thought to act in concert to promote tumor suppression and tissue aging. While chromatin regulation and down regulation of lamin B1 have been implicated as effectors of cell senescence, functional interactions between them are poorly understood. We compared the genome-wide distributions of H3K4me3 and H3K27me3 between proliferating and senescent primary human cells and found dramatic differences, including large-scale domains of H3K4me3- and H3K27me3-enriched “mesas” and H3K27me3-depleted “canyons” in senescent cells. Senescent mesas form at the sites of lamin B1-associated domains (LADs) in proliferating cells. Mesas also overlap with regions that exhibit DNA hypomethylation in cancer, suggesting that chromatin changes in pre-malignant senescent cells foreshadow epigenetic changes in cancer. Proliferating fibroblasts from Hutchinson-Gilford Progeria Syndrome patients expressing mutant lamin A (progerin) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence and tissue aging. In contrast, canyons form mostly in between LADs and are enriched in genes, gene promoters and enhancers. Strikingly, H3K27me3 loss in canyons is correlated with upregulation of key senescence genes, including genes comprising the SASP, indicating a link between global changes in chromatin structure and local regulation of gene expression. Finally, premature reduction of lamin B1 in midlife proliferating cells triggers formation of senescence-associated mesas and canyons and accelerated senescence. Together, our data illustrate a profound reorganization of chromatin during senescence, and suggest that down regulation of lamin B1 in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging and cancer.

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Genome-wide mapping of H4K20me3 in proliferating and senescent IMR90 cells.

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