Article abstract
Nature Structural & Molecular Biology 15, 1176 - 1183 (2008)
Published online: 26 October 2008 | doi:10.1038/nsmb.1476
De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes
Silvina Epsztejn-Litman1,5, Nirit Feldman1,5, Monther Abu-Remaileh1,5, Yoel Shufaro2, Ariela Gerson1, Jun Ueda3, Rachel Deplus4, François Fuks4, Yoichi Shinkai3, Howard Cedar1 & Yehudit Bergman1
Abstract
The pluripotency-determining gene Oct3/4 (also called Pou5f1) undergoes postimplantation silencing in a process mediated by the histone methyltransferase G9a. Microarray analysis now shows that this enzyme may operate as a master regulator that inactivates numerous early-embryonic genes by bringing about heterochromatinization of methylated histone H3K9 and de novo DNA methylation. Genetic studies in differentiating embryonic stem cells demonstrate that a point mutation in the G9a SET domain prevents heterochromatinization but still allows de novo methylation, whereas biochemical and functional studies indicate that G9a itself is capable of bringing about de novo methylation through its ankyrin domain, by recruiting Dnmt3a and Dnmt3b independently of its histone methyltransferase activity. These modifications seem to be programmed for carrying out two separate biological functions: histone methylation blocks target-gene reactivation in the absence of transcriptional repressors, whereas DNA methylation prevents reprogramming to the undifferentiated state.
- Departments of Experimental Medicine and Cellular Biochemistry, Hebrew University Medical School, Ein Kerem, Jerusalem 91120, Israel.
- IVF Unit, The Department of OB/GYN, The Hadassah Human Embryonic Stem Cell Research Center, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
- Experimental Research Center for Infectious Disease, Institute for Virus Research, Kyoto University, Sakyo-Ku, Kyoto 606-8507, Japan.
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Free University of Brussels, Brussels 1070, Belgium.
- These authors contributed equally to this work.
Correspondence to: Howard Cedar1 e-mail: cedar@cc.huji.ac.il
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