Hargan-Calvopina Joseph, Taylor Sara, Cook Helene, Hu Zhongxun, Lee Serena A, Yen Ming-Ren, Chiang Yih-Shien, Chen Pao-Yang, Clark Amander T
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Institute of Plant and Microbial Biology, Academia Sinica, Taipei 11529, Taiwan.
Dev Cell. 2016 Oct 10;39(1):75-86. doi: 10.1016/j.devcel.2016.07.019. Epub 2016 Sep 9.
Remodeling DNA methylation in mammalian genomes can be global, as seen in preimplantation embryos and primordial germ cells (PGCs), or locus specific, which can regulate neighboring gene expression. In PGCs, global and locus-specific DNA demethylation occur in sequential stages, with an initial global decrease in methylated cytosines (stage I) followed by a Tet methylcytosine dioxygenase (Tet)-dependent decrease in methylated cytosines that act at imprinting control regions (ICRs) and meiotic genes (stage II). The purpose of the two-stage mechanism is unclear. Here we show that Dnmt1 preserves DNA methylation through stage I at ICRs and meiotic gene promoters and is required for the pericentromeric enrichment of 5hmC. We discovered that the functional consequence of abrogating two-stage DNA demethylation in PGCs was precocious germline differentiation leading to hypogonadism and infertility. Therefore, bypassing stage-specific DNA demethylation has significant consequences for progenitor germ cell differentiation and the ability to transmit DNA from parent to offspring.
哺乳动物基因组中DNA甲基化的重塑可以是全局性的，如在植入前胚胎和原始生殖细胞（PGC）中所见，也可以是位点特异性的，后者可调节邻近基因的表达。在PGC中，全局性和位点特异性DNA去甲基化按顺序分阶段发生，最初是甲基化胞嘧啶的全局性减少（第一阶段），随后是在印记控制区域（ICR）和减数分裂基因处依赖于Tet甲基胞嘧啶双加氧酶（Tet）的甲基化胞嘧啶减少（第二阶段）。两阶段机制的目的尚不清楚。在这里，我们表明Dnmt1在ICR和减数分裂基因启动子处通过第一阶段维持DNA甲基化，并且是5hmC着丝粒周围富集所必需的。我们发现，在PGC中废除两阶段DNA去甲基化的功能后果是生殖系过早分化，导致性腺功能减退和不育。因此，绕过阶段特异性DNA去甲基化对祖代生殖细胞分化以及将DNA从亲代传递给后代的能力具有重大影响。
