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

Agustin Chicas, Avnish Kapoor, Xiaowo Wang, Ozlem Aksoy, Adam G. Evertts, Michael Q. Zhang, Benjamin A. Garcia, Emily Bernstein, Scott W. Lowe

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

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.

Original languageEnglish
Pages (from-to)8971-8976
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number23
DOIs
StatePublished - Jun 5 2012

Keywords

  • H3K4me3
  • Histone demethylase

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