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Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8971-6. doi: 10.1073/pnas.1119836109. Epub 2012 May 21.

H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence.

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  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Abstract

Cellular senescence is a tumor-suppressive program that involves chromatin reorganization and specific changes in gene expression that trigger an irreversible cell-cycle arrest. Here we combine quantitative mass spectrometry, ChIP deep-sequencing, and functional studies to determine the role of histone modifications on chromatin structure and gene-expression alterations associated with senescence in primary human cells. We uncover distinct senescence-associated changes in histone-modification patterns consistent with a repressive chromatin environment and link the establishment of one of these patterns--loss of H3K4 methylation--to the retinoblastoma tumor suppressor and the H3K4 demethylases Jarid1a and Jarid1b. Our results show that Jarid1a/b-mediated H3K4 demethylation contributes to silencing of retinoblastoma target genes in senescent cells, suggesting a mechanism by which retinoblastoma triggers gene silencing. Therefore, we link the Jarid1a and Jarid1b demethylases to a tumor-suppressor network controlling cellular senescence.

PMID:
22615382
[PubMed - indexed for MEDLINE]
PMCID:
PMC3384172
Free PMC Article

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