G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis

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Abstract

Oct-3/4 is a POU domain homeobox gene that is expressed during gametogenesis and in early embryonic cells1,2, where it has been shown to be important for maintaining pluripotency3. 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.

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Figure 1: Programmed inactivation of Oct-3/4 in P19 cells.
Figure 2: Heterochromatinization of Oct-3/4 and Rex-1.
Figure 3: Role of Dnmt3a/3b in Oct-3/4 repression.
Figure 4: G9a-mediated Oct-3/4 H3(K9) methylation.
Figure 5: Chromatin structure affects reversal of ES cell differentiation.

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Acknowledgements

We are grateful to T. Jenuwein for his cooperation. This work was supported by grants from the Israel Academy of Sciences (Y.B. and H.C.), Philip Morris USA Inc. and Philip Morris International (Y.B. and H.C), the National Institutes of Health (Y.Z., Y.B. and H.C.), the European Community 5th Framework Quality of Life Program (Y.B.), The American Cancer Society (Y.Z.), the Israel Cancer Research Fund (H.C.) and the Prostate Cancer Foundation (H.C.).

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Correspondence to Yehudit Bergman.

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