Jarid1b targets genes regulating development and is involved in neural differentiation.
H3K4 methylation is associated with active transcription and in combination with H3K27me3 thought to keep genes regulating development in a poised state. The contribution of enzymes regulating trimethylation of lysine 4 at histone 3 (H3K4me3) levels to embryonic stem cell (ESC) self-renewal and differentiation is just starting to emerge. Here, we show that the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) is dispensable for ESC self-renewal, but essential for ESC differentiation along the neural lineage. By genome-wide location analysis, we demonstrate that Jarid1b localizes predominantly to transcription start sites of genes encoding developmental regulators, of which more than half are also bound by Polycomb group proteins. Virtually all Jarid1b target genes are associated with H3K4me3 and depletion of Jarid1b in ESCs leads to a global increase of H3K4me3 levels. During neural differentiation, Jarid1b-depleted ESCs fail to efficiently silence lineage-inappropriate genes, specifically stem and germ cell genes. Our results delineate an essential role for Jarid1b-mediated transcriptional control during ESC differentiation.
Biotech Research and Innovation Centre, University of Copenhagen, Denmark.
Sandra U
SU
Schmitz
Mareike
M
Albert
Martina
M
Malatesta
Lluis
L
Morey
Jens V
JV
Johansen
Mads
M
Bak
Niels
N
Tommerup
Iratxe
I
Abarrategui
Kristian
K
Helin
D000818:Animals; D000911:Antibodies, Monoclonal; D002460:Cell Line; D002490:Central Nervous System / Q000196:embryology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques / Q000379:methods; D006657:Histones / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic
D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D006657:Histones; D063146:Polycomb-Group Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C485614:Kdm5b protein, mouse