G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis.
Oct-3/4 is a POU domain homeobox gene that is expressed during gametogenesis and in early embryonic cells, where it has been shown to be important for maintaining pluripotency. Following implantation, this gene undergoes a novel multi-step programme of inactivation. Transcriptional repression is followed by a pronounced increase in histone H3 methylation on Lys 9 that is mediated by the SET-containing protein, G9a. This step sets the stage for local heterochromatinization via the binding of HP1 and is required for subsequent de novo methylation at the promoter by the enzymes Dnmt3a/3b. Genetic studies show that these epigenetic changes actually have an important role in the inhibition of Oct-3/4 re-expression, thereby preventing reprogramming.
Feldman
Nirit
N
Department of Experimental Medicine, Hebrew University Medical School, Ein Kerem, Jerusalem 91120, Israel.
Gerson
Ariela
A
Fang
Jia
J
Li
En
E
Zhang
Yi
Y
Shinkai
Yoichi
Y
Cedar
Howard
H
Bergman
Yehudit
Y
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics* / Q000502:physiology; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006570:Heterochromatin / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D008745:Methylation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011496:Protein Methyltransferases; D014212:Tretinoin / Q000494:pharmacology; D000097584:DNA Methyltransferase 3B
D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D011496:Protein Methyltransferases; D014212:Tretinoin; D000097584:DNA Methyltransferase 3B; C000715535:Dnmt3a protein, mouse; C475540:Nanog protein, mouse