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.