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

作者：Chicas Agustin; Kapoor Avnish; Wang Xiaowo; Aksoy Ozlem; Evertts Adam G; Zhang Michael Q; Garcia Benjamin A; Bernstein Emily^*; Lowe Scott W

来源：Proceedings of the National Academy of Sciences, 2012, 109(23): 8971-8976.

DOI：10.1073/pnas.1119836109

• H3K4me3
• histone demethylase

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.

• 出版日期2012-6-5
• 单位清华大学