title: Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation.
abstract: Epigenetic regulation underlies the robust changes in gene expression that occur during development. How precisely epigenetic enzymes contribute to development and differentiation processes is largely unclear. Here we show that one of the enzymes that removes the activating epigenetic mark of trimethylated lysine 4 on histone H3, lysine (K)-specific demethylase 5A (KDM5A), reinforces the effects of the retinoblastoma (RB) family of transcriptional repressors on differentiation. Global location analysis showed that KDM5A cooccupies a substantial portion of target genes with the E2F4 transcription factor. During ES cell differentiation, knockout of KDM5A resulted in derepression of multiple genomic loci that are targets of KDM5A, denoting a direct regulatory function. In terminally differentiated cells, common KDM5A and E2F4 gene targets were bound by the pRB-related protein p130, a DREAM complex component. KDM5A was recruited to the transcription start site regions independently of E2F4; however, it cooperated with E2F4 to promote a state of deepened repression at cell cycle genes during differentiation. These findings reveal a critical role of H3K4 demethylation by KDM5A in the transcriptional silencing of genes that are suppressed by RB family members in differentiated cells.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL 60607, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Beshiri
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Holmes
authors.forename: William F
authors.initials: WF
authors.lastname: Richter
authors.forename: Samuel
authors.initials: S
authors.lastname: Hess
authors.forename: Abul B M M K
authors.initials: AB
authors.lastname: Islam
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.forename: Lydia
authors.initials: L
authors.lastname: Plante
authors.forename: Larisa
authors.initials: L
authors.lastname: Litovchick
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gévry
authors.forename: Nuria
authors.initials: N
authors.lastname: Lopez-Bigas
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.forename: Elizaveta V
authors.initials: EV
authors.lastname: Benevolenskaya
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D050704:E2F4 Transcription Factor / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D018816:Genes, cdc / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D056485:Retinoblastoma-Binding Protein 2 / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D050704:E2F4 Transcription Factor; D006657:Histones; D046912:Multiprotein Complexes; D012097:Repressor Proteins; C070050:KDM5A protein, human; C577458:KDM5A protein, mouse; D056485:Retinoblastoma-Binding Protein 2; D008239:Lysine