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The pluripotency gene  Oct4  encodes a key transcription factor that maintains self‐renewal of embryonic stem cell (ESC) and is downregulated upon differentiation of ESCs and silenced in somatic cells. A combination of  cis  elements, transcription factors, and epigenetic modifications, such as DNA methylation, mediates  Oct4  gene expression. Here, we show that the orphan nuclear receptor germ cell nuclear factor (GCNF) initiates  Oct4  repression and DNA methylation by the differential recruitment of methyl‐CpG binding domain (MBD) and DNA methyltransferases (Dnmts) to the  Oct4  promoter. When compared with wild‐type ESCs and gastrulating embryos,  Oct4  repression is lost and its proximal promoter is significantly hypomethylated in retinoic acid (RA)‐differentiated  GCNF  −/−  ESCs and  GCNF  −/−  embryos. Efforts to characterize mediators of GCNF's repressive function and DNA methylation of the  Oct4  promoter identified MBD3, MBD2, and de novo Dnmts as GCNF interacting factors. Upon differentiation, endogenous GCNF binds to the  Oct4  proximal promoter and differentially recruits MBD3 and MBD2 as well as Dnmt3A. In differentiated  GCNF  −/−  ESCs, recruitment of MBD3 and MBD2 as well as Dnmt3A to Oct4 promoter is lost and subsequently Oct4 repression and DNA methylation failed to occur. Hypomethylation of the Oct4 promoter is also observed in RA‐differentiated  MBD3  −/−  and  Dnmt3A  −/−  ESCs, but not in  MBD2  −/−  and  Dnmt3B  −/−  ESCs. Thus, recruitment of MBD3, MBD2, and Dnmt3A by GCNF links two events: gene‐specific repression and DNA methylation, which occur differentially at the  Oct4  promoter. GCNF initiates the repression and epigenetic modification of  Oct4  gene during ESC differentiation. S TEM  C ELLS  2011;29:1041–1051

stem cells

Differential Recruitment of Methyl CpG‐Binding Domain Factors and DNA Methyltransferases by the Orphan Receptor Germ Cell Nuclear Factor Initiates the Repression and Silencing of  Oct4