Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells.
Embryonic stem (ES) cells are pluripotent cells with the ability to self-renew indefinitely. These unique properties are controlled by genetic factors and chromatin structure. The exit from the self-renewing state is accompanied by changes in epigenetic chromatin modifications such as an induction in the silencing-associated histone H3 Lys 9 dimethylation and trimethylation (H3K9Me2/Me3) marks. Here, we show that the H3K9Me2 and H3K9Me3 demethylase genes, Jmjd1a and Jmjd2c, are positively regulated by the ES cell transcription factor Oct4. Interestingly, Jmjd1a or Jmjd2c depletion leads to ES cell differentiation, which is accompanied by a reduction in the expression of ES cell-specific genes and an induction of lineage marker genes. Jmjd1a demethylates H3K9Me2 at the promoter regions of Tcl1, Tcfcp2l1, and Zfp57 and positively regulates the expression of these pluripotency-associated genes. Jmjd2c acts as a positive regulator for Nanog, which encodes for a key transcription factor for self-renewal in ES cells. We further demonstrate that Jmjd2c is required to reverse the H3K9Me3 marks at the Nanog promoter region and consequently prevents transcriptional repressors HP1 and KAP1 from binding. Our results connect the ES cell transcription circuitry to chromatin modulation through H3K9 demethylation in pluripotent cells.
Loh
Yuin-Han
YH
Gene Regulation Laboratory, Genome Institute of Singapore, Singapore 138672.
Zhang
Weiwei
W
Chen
Xi
X
George
Joshy
J
Ng
Huck-Hui
HH
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000201:enzymology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference
D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C511045:Kdm3a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D008239:Lysine