Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells.
Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells.
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DOI：
10.1101/gad.244848.114
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发表时间：
2014-09-15
影响因子：
10.5
通讯作者：
Lorincz MC
中科院分区：
文献类型：
--
作者：
Liu S;Brind'Amour J;Karimi MM;Shirane K;Bogutz A;Lefebvre L;Sasaki H;Shinkai Y;Lorincz MC
内源性逆转录病毒的转录在配子发生过程中受到从头DNA甲基化的抑制，并且DNA甲基化在两种性别的E13.5原始生殖细胞（PGCs）中达到低点。Liu等人发现，H3 K9甲基转移酶SETDB 1的种系特异性条件敲除产生H3 K9 me 3和H3 K27 me 3标记的减少以及H3 K9 me 3富集的逆转录转座子家族的DNA甲基化。Setdb 1缺乏与男性E13.5 PGCs数量减少和出生后性腺功能减退有关。因此，SETDB 1是在生殖系中从头DNA甲基化开始之前对抗前病毒表达的重要监护人。内源性逆转录病毒（ERVs）的转录在配子发生过程中受到从头DNA甲基化的抑制，配子发生是一个在卵母细胞出生后开始的过程，在胚胎发育的第15.5天（E15.5）左右。在种系发育的早期，基因组，包括大多数逆转录转座子，逐渐去甲基化。然而，年轻的ERVK和ERV 1元件保留中间甲基化水平。由于DNA甲基化在两种性别的E13.5原始生殖细胞（PGC）中达到低点，我们使用最近开发的低输入ChIP-seq（染色质免疫沉淀[ChIP]结合深度测序）方法确定逆转录转座子是否被H3 K9 me 3和H3 K27 me 3标记。虽然这些抑制性组蛋白修饰主要存在于E13.5 PGC的不同基因组区域，但它们同时标记部分甲基化的长末端重复序列（LTR）和LINE 1元件。H3 K9甲基转移酶SETDB 1的种系特异性条件性敲除导致富含H3 K9 me 3的逆转录转座子家族的标记和DNA甲基化均减少。引人注目的是，Setdb 1敲除E13.5 PGC显示伴随的许多标记ERV的去抑制，包括脑池内A颗粒（IAP），ETn，ERVK 10 C元件，和ERV近端基因，一个子集在性别依赖的方式。此外，Setdb 1缺陷与男性E13.5 PGCs数量减少和出生后性腺功能减退有关。综上所述，这些观察结果表明，SETDB 1是一个重要的监护人对前病毒的表达之前，在生殖细胞中的从头DNA甲基化。
Transcription of endogenous retroviruses is inhibited by de novo DNA methylation during gametogenesis, and DNA methylation reaches a low point in E13.5 primordial germ cells (PGCs) of both sexes. Liu et al. find that germline-specific conditional knockout of the H3K9 methyltransferase SETDB1 yields a decrease of H3K9me3 and H3K27me3 marks and DNA methylation at H3K9me3-enriched retrotransposon families. Setdb1 deficiency is associated with a reduced number of male E13.5 PGCs and postnatal hypogonadism in both sexes. Therefore, SETDB1 is an essential guardian against proviral expression prior to the onset of de novo DNA methylation in the germline. Transcription of endogenous retroviruses (ERVs) is inhibited by de novo DNA methylation during gametogenesis, a process initiated after birth in oocytes and at approximately embryonic day 15.5 (E15.5) in prospermatogonia. Earlier in germline development, the genome, including most retrotransposons, is progressively demethylated. Young ERVK and ERV1 elements, however, retain intermediate methylation levels. As DNA methylation reaches a low point in E13.5 primordial germ cells (PGCs) of both sexes, we determined whether retrotransposons are marked by H3K9me3 and H3K27me3 using a recently developed low-input ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) method. Although these repressive histone modifications are found predominantly on distinct genomic regions in E13.5 PGCs, they concurrently mark partially methylated long terminal repeats (LTRs) and LINE1 elements. Germline-specific conditional knockout of the H3K9 methyltransferase SETDB1 yields a decrease of both marks and DNA methylation at H3K9me3-enriched retrotransposon families. Strikingly, Setdb1 knockout E13.5 PGCs show concomitant derepression of many marked ERVs, including intracisternal A particle (IAP), ETn, and ERVK10C elements, and ERV-proximal genes, a subset in a sex-dependent manner. Furthermore, Setdb1 deficiency is associated with a reduced number of male E13.5 PGCs and postnatal hypogonadism in both sexes. Taken together, these observations reveal that SETDB1 is an essential guardian against proviral expression prior to the onset of de novo DNA methylation in the germline.
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影响因子：
64.8
作者：
Hajkova, Petra;Ancelin, Katia;Waldmann, Tanja;Lacoste, Nicolas;Lange, Ulrike C.;Cesari, Francesca;Lee, Caroline;Almouzni, Genevieve;Schneider, Robert;Surani, M. Azim
通讯作者：
Surani, M. Azim
DOI：
10.1126/science.1229277
发表时间：
2013-01-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hackett JA;Sengupta R;Zylicz JJ;Murakami K;Lee C;Down TA;Surani MA
通讯作者：
Surani MA
影响因子：
4.5
作者：
Kobayashi H;Sakurai T;Imai M;Takahashi N;Fukuda A;Yayoi O;Sato S;Nakabayashi K;Hata K;Sotomaru Y;Suzuki Y;Kono T
通讯作者：
Kono T
DOI：
10.1038/nrg3355
发表时间：
2013-02
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Alder, Olivia;Lavial, Fabrice;Azuara, Veronique
通讯作者：
Azuara, Veronique