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NSD1负责的H3K36me2指导小鼠雄性生殖系中的从头甲基化
2020-09-17 15:12

加拿大英属哥伦比亚大学Matthew C. Lorincz研究组近期发现,NSD1负责的H3K36me2指导小鼠雄性生殖系中的从头甲基化,并抵消了Polycomb相关的沉默。2020年9月14日,国际知名学术期刊《自然—遗传学》在线发表了这一成果。

研究人员表示,哺乳动物生殖细胞中的从头DNA甲基化(DNAme)取决于DNMT3A和DNMT3L。然而,卵母细胞和精子显示出不同的DNAme模式。在小鼠卵母细胞中,从头DNAme需要赖氨酸甲基转移酶(KMTase)SETD2,该酶负责H3K36me3。

研究人员发现,SETD2对于雄性生殖系中的新生DNAme是可有可无的。取而代之的是,赖氨酸甲基转移酶NSD1在常染色体区域广泛修饰H3K36me2,它在prospermatogonia中的DNAme里起着至关重要的作用,包括在印迹基因中。但是,生殖系NSD1缺乏的雄性比Dnmt3l-/-雄性显示出更严重的精子发生缺陷。

值得注意的是,与DNMT3L不同,NSD1可以保护一部分基因免受H3K27me3相关的转录沉默的影响。相反,卵母细胞中的H3K36me2主要依赖于SETD2,并且与H3K36me3一致。此外,具有NSD1缺陷卵母细胞的雌性可育。因此,在成熟的小鼠配子中,DNAme的性二态性模式是由H3K36甲基化的不同特征所编排的。

附:英文原文

Title: NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing

Author: Kenjiro Shirane, Fumihito Miura, Takashi Ito, Matthew C. Lorincz

Issue&Volume: 2020-09-14

Abstract: 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 than Dnmt3l/ 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.

DOI: 10.1038/s41588-020-0689-z

Source: https://www.nature.com/articles/s41588-020-0689-z

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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