NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing
NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing
复制标题
DOI：
10.1038/s41588-020-0689-z
复制
发表时间：
2020-09-14
期刊：
影响因子：
30.8
通讯作者：
Lorincz, Matthew C.
中科院分区：
文献类型：
--
作者：
Shirane, Kenjiro;Miura, Fumihito;Lorincz, Matthew C.
哺乳动物生殖细胞中的从头DNA甲基化(DNAME)依赖于DNMT3A和DNMT3L。然而，卵母细胞和精子表现出不同的DNAME模式。在小鼠卵母细胞中，从头开始DNAME需要赖氨酸甲基转移酶(KMTase)SETD2，它会沉积H3K36me3。我们在这里表明，在雄性生殖系中，SETD2对于从头开始的DNAME是必不可少的。相反，赖氨酸甲基转移酶NSD1在常染色质区域广泛沉积H3K36me2，在包括印记基因在内的繁荣原细胞的从头DNAME中发挥关键作用。然而，缺乏生殖系NSD1的雄性在精子发生方面表现出比Dnmt3(-/-)雄性更严重的缺陷。值得注意的是，与DNMT3L不同，NSD1保护一部分基因免受H3K27me3相关的转录沉默。相反，卵母细胞中的H3K36me2主要依赖于SETD2，并且与H3K36me3重合。此外，具有NSD1缺陷卵母细胞的雌性是有生育能力的。因此，成熟小鼠配子中DNAME的性别二态模式是由不同的H3K36甲基化谱调控的。NSD1沉积H3K36me2，是雄性DNA甲基化的主要调节因子，但在雌性配子发生中不是。NSD1对H3K27me3相关的转录沉默具有保护作用。
De novo DNA methylation (DNAme) in mammalian germ cells is dependent on DNMT3A and DNMT3L. However, oocytes and spermatozoa show distinct patterns of DNAme. In mouse oocytes, de novo DNAme requires the lysine methyltransferase (KMTase) SETD2, which deposits H3K36me3. We show here that SETD2 is dispensable for de novo DNAme in the male germline. Instead, the lysine methyltransferase NSD1, which broadly deposits H3K36me2 in euchromatic regions, plays a critical role in de novo DNAme in prospermatogonia, including at imprinted genes. However, males deficient in germline NSD1 show a more severe defect in spermatogenesis thanDnmt3l(-/-)males. Notably, unlike DNMT3L, NSD1 safeguards a subset of genes against H3K27me3-associated transcriptional silencing. In contrast, H3K36me2 in oocytes is predominantly dependent on SETD2 and coincides with H3K36me3. Furthermore, females with NSD1-deficient oocytes are fertile. Thus, the sexually dimorphic pattern of DNAme in mature mouse gametes is orchestrated by distinct profiles of H3K36 methylation.NSD1, which deposits H3K36me2, is a major regulator of DNA methylation in male but not in female gametogenesis. NSD1 safeguards against H3K27me3-associated transcriptional silencing.