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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Dong, Kevin B. Appanah, Ruth Rossi, Fabio Tachibana, Makoto Mager, Dixie L. Lee, Sandra Goyal, Preeti Shinkai, Yoichi Lehnertz, Bernhard Leung, Danny C. Lorincz, Matthew C. Maksakova, Irina A. |
| Description | Author Affiliation: Leung DC ( Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.); |
| Abstract | Methylation on lysine 9 of histone H3 (H3K9me) and DNA methylation play important roles in the transcriptional silencing of specific genes and repetitive elements. Both marks are detected on class I and II endogenous retroviruses (ERVs) in murine embryonic stem cells (mESCs). Recently, we reported that the H3K9-specific lysine methyltransferase (KMTase) Eset/Setdb1/KMT1E is required for H3K9me3 and the maintenance of silencing of ERVs in mESCs. In contrast, G9a/Ehmt2/KMT1C is dispensable, despite the fact that this KMTase is required for H3K9 dimethylation (H3K9me2) and efficient DNA methylation of these retroelements. Transcription of the exogenous retrovirus (XRV) Moloney murine leukemia virus is rapidly extinguished after integration in mESCs, concomitant with de novo DNA methylation. However, the role that H3K9 KMTases play in this process has not been addressed. Here, we demonstrate that G9a, but not Suv39h1 or Suv39h2, is required for silencing of newly integrated Moloney murine leukemia virus-based vectors in mESCs. The silencing defect in G9a(-/-) cells is accompanied by a reduction of H3K9me2 at the proviral LTR, indicating that XRVs are direct targets of G9a. Furthermore, de novo DNA methylation of newly integrated proviruses is impaired in the G9a(-/-) line, phenocopying proviral DNA methylation and silencing defects observed in Dnmt3a-deficient mESCs. Once established, however, maintenance of silencing of XRVs, like ERVs, is dependent exclusively on the KMTase Eset. Taken together, these observations reveal that in mESCs, the H3K9 KMTase G9a is required for the establishment, but not for the maintenance, of silencing of newly integrated proviruses. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 14 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | DNA Methylation Genetics Embryonic Stem Cells Virology Histone-Lysine N-Methyltransferase Metabolism Moloney Murine Leukemia Virus Animals Blotting, Western Chromatin Immunoprecipitation DNA (Cytosine-5-)-Methyltransferase Endogenous Retroviruses Flow Cytometry Gene Silencing Genetic Vectors Mice Mice, Knockout Proviruses Reverse Transcriptase Polymerase Chain Reaction Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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