Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 23, Pages 8971-8976Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1119836109
Keywords
H3K4me3; histone demethylase
Categories
Funding
- National Science Foundation of China [60905013, 91019016, 31061160497]
- National Institutes of Health (NIH) [5F32AG027631, R21CA150117-01, HG001696, AG16379]
- Department of Defense [W81XWH-11-1-0019]
- Office of the Director of the NIH [DP2OD007447]
- National Science Foundation
- New Jersey Cancer Commission on Research
- Ellison Medical Foundation
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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.
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