The orphan nuclear receptor GCNF recruits DNA methyltransferase for Oct-3/4 silencing.
Somatic DNA methylation patterns are determined in part by the de novo methylation that occurs after early embryonic demethylation. Oct-3/4, a pluripotency gene, is unmethylated in the blastocyst, but undergoes de novo methylation and silencing during gastrulation. Here we show that the transcriptional repressor GCNF recruits DNA methyltransferase to the Oct-3/4 promoter and facilitates its methylation. Although acetylation of histone H3 at lysine 9 (K9) and/or 14 (K14) and methylation of H3 at lysine 4 (K4) decrease during this period, as do Oct-3/4 transcript levels, H3K9 and H3K27 methylation levels remain constant, indicating that DNA methylation does not require repressive histone modifications. We found that GCNF interacts directly with Dnmt3 molecule(s) and verified that this interaction induces the methylation of the Oct-3/4 promoter. Our finding suggests a model in which differentiation-induced GCNF recruits de novo DNA methyltransferase and facilitates the silencing of a pluripotency gene.
Sato
Noriko
N
Cytokine Project, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan. nrksato@rinshoken.or.jp
Kondo
Mitsumasa
M
Arai
Ken-ichi
K
D000818:Animals; D002478:Cells, Cultured; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020868:Gene Silencing / Q000502:physiology*; D051379:Mice; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D000099254:Organic Cation Transporter 3
D015254:DNA Modification Methylases; D004268:DNA-Binding Proteins; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D050814:Octamer Transcription Factor-3; D027701:Organic Cation Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000099254:Organic Cation Transporter 3; C539954:Nr6a1 protein, mouse; C494174:Pou5f1 protein, mouse