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Nature doi:10.1038/nature08858;7 _) C a$ o- K3 ?
: _, E. f- B, N$ W3 ^Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET
6 J8 I5 r- n' M8 n% {/ \Toshiyuki Matsui1,2,5, Danny Leung3,5, Hiroki Miyashita1,2, Irina A. Maksakova3, Hitoshi Miyachi1, Hiroshi Kimura4, Makoto Tachibana1,2, Matthew C. Lorincz3 & Yoichi Shinkai1,2( D# h0 v9 b/ W9 c: f( D
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1Experimental Research Center for Infectious Diseases, Institute for Virus Research, and," }; h3 n* ]; {% u+ j; n7 b
2Graduate School of Biostudies, Kyoto University, 53 Shogoin, Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan0 ]1 e, w' d& U
3Department of Medical Genetics, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
" w2 ?; z) w9 s' R& y7 r+ a4Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan' i W# {7 l2 A; E/ |$ w
5These authors contributed equally to this work.
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Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising ~10% of the mouse genome1. These parasitic elements are responsible for >10% of spontaneous mutations2. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells3, 4, 5, an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV)6, 7, 8. Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts9. However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Krüppel-associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28)10, 11 are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (Dnmt1-/-Dnmt3a-/-Dnmt3b-/-) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed. |
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发表于 2010-5-5 23:30
发表于 2010-5-16 15:10
