H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence.
Proc Natl Acad Sci U S A, 2012/6/05;109(23):8971-6.
Chicas A[1], Kapoor A, Wang X, Aksoy O, Evertts AG, Zhang MQ, Garcia BA, Bernstein E, Lowe SW
Affiliations
PMID: 22615382DOI: 10.1073/pnas.1119836109
Impact factor: 12.779
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.
MeSH terms
Cell Line; Cellular Senescence; Chromatin; Chromatin Immunoprecipitation; Gene Expression Regulation; Gene Silencing; Genetic Vectors; High-Throughput Nucleotide Sequencing; Histones; Humans; Immunoblotting; Jumonji Domain-Containing Histone Demethylases; Mass Spectrometry; Methylation; Nuclear Proteins; Repressor Proteins; Retinoblastoma-Binding Protein 2; Retroviridae; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA
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