title: H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence.
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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Agustin
authors.initials: A
authors.lastname: Chicas
authors.forename: Avnish
authors.initials: A
authors.lastname: Kapoor
authors.forename: Xiaowo
authors.initials: X
authors.lastname: Wang
authors.forename: Ozlem
authors.initials: O
authors.lastname: Aksoy
authors.forename: Adam G
authors.initials: AG
authors.lastname: Evertts
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Zhang
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.forename: Emily
authors.initials: E
authors.lastname: Bernstein
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation / Q000235:genetics*; D020868:Gene Silencing / Q000502:physiology*; D005822:Genetic Vectors; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D013058:Mass Spectrometry; D008745:Methylation; D009687:Nuclear Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D056485:Retinoblastoma-Binding Protein 2 / Q000378:metabolism*; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C070050:KDM5A protein, human; C119611:KDM5B protein, human; D056485:Retinoblastoma-Binding Protein 2