title: Balancing of histone H3K4 methylation states by the Kdm5c/SMCX histone demethylase modulates promoter and enhancer function.
abstract: The functional organization of eukaryotic genomes correlates with specific patterns of histone methylations. Regulatory regions in genomes such as enhancers and promoters differ in their extent of methylation of histone H3 at lysine-4 (H3K4), but it is largely unknown how the different methylation states are specified and controlled. Here, we show that the Kdm5c/Jarid1c/SMCX member of the Kdm5 family of H3K4 demethylases can be recruited to both enhancer and promoter elements in mouse embryonic stem cells and in neuronal progenitor cells. Knockdown of Kdm5c deregulates transcription via local increases in H3K4me3. Our data indicate that by restricting H3K4me3 modification at core promoters, Kdm5c dampens transcription, but at enhancers Kdm5c stimulates their activity. Remarkably, an impaired enhancer function activates the intrinsic promoter activity of Kdm5c-bound distal elements. Our results demonstrate that the Kdm5c demethylase plays a crucial and dynamic role in the functional discrimination between enhancers and core promoters.
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: Nikolay S
authors.initials: NS
authors.lastname: Outchkourov
authors.forename: Jose M
authors.initials: JM
authors.lastname: Muiño
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kaufmann
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van Ijcken
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Groot Koerkamp
authors.forename: Dik
authors.initials: D
authors.lastname: van Leenen
authors.forename: Petra
authors.initials: P
authors.lastname: de Graaf
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
authors.forename: Frank G
authors.initials: FG
authors.lastname: Grosveld
authors.forename: H T Marc
authors.initials: HT
authors.lastname: Timmers
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D053595:Embryonic Stem Cells; D056466:Histone Demethylases; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C494113:Elk1 protein, mouse; D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050807:ets-Domain Protein Elk-1; D056466:Histone Demethylases; C490173:Kdm5c protein, mouse; D010089:Oxidoreductases, N-Demethylating