Stage-Specific Demethylation in Primordial Germ Cells Safeguards against Precocious Differentiation.
Stage-Specific Demethylation in Primordial Germ Cells Safeguards against Precocious Differentiation.
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DOI：
10.1016/j.devcel.2016.07.019
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发表时间：
2016-10-10
影响因子：
11.8
通讯作者：
Clark, Amander T.
中科院分区：
文献类型：
--
作者：
Hargan-Calvopina, Joseph;Taylor, Sara;Cook, Helene;Hu, Zhongxun;Lee, Serena A.;Yen, Ming-Ren;Chiang, Yih-Shien;Chen, Pao-Yang;Clark, Amander T.
哺乳动物基因组中的DNA甲基化重构可以是全球性的，如着床前胚胎和原始生殖细胞（PGCs），也可以是位点特异性的，它可以调节邻近基因的表达。在PGCs中，整体的和位点特异性的DNA去甲基化发生在连续的阶段，初始的甲基化胞嘧啶整体减少（阶段I），随后在印迹控制区（ICRs）和减数分裂基因上作用的甲基化胞嘧啶双加氧酶（Tet）依赖的甲基化胞嘧啶减少（阶段II）。两阶段机制的目的尚不清楚。在这里，我们发现Dnmt1在ICRs和减数分裂基因启动子的I期保持DNA甲基化，并且是5hmC在中心点周围富集所必需的。我们发现，在PGCs中取消两阶段DNA去甲基化的功能后果是生殖系分化早熟，导致性腺功能减退和不育。因此，绕过特定阶段的DNA去甲基化对祖生殖细胞分化和将DNA从亲本传递给后代的能力具有重要影响。Hargan-Calvopina等人阐明了原始生殖细胞中两阶段DNA去甲基化的功能意义——一种全球性的减少，随后是位点特异性的丧失。Dnmt1在特定位点保留了I期的DNA甲基化，包括中心点周围区域。取消这两个阶段会导致生殖细胞分化过早，导致性腺功能减退和不孕。
Remodeling DNA methylation in mammalian genomes can be global as seen in pre-implantation 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. Hargan-Calvopina et al. shed light on functional significance of two-stage DNA demethylation – a global decrease followed by locus-specific loss – in primordial germ cells. Dnmt1 preserves DNA methylation in stage I at specific loci, including pericentromeric regions. Abrogating the two-stages results in precocious germline differentiation, leading to hypogonadism and infertility.
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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：
10.5
作者：
Liu S;Brind'Amour J;Karimi MM;Shirane K;Bogutz A;Lefebvre L;Sasaki H;Shinkai Y;Lorincz MC
通讯作者：
Lorincz MC
影响因子：
64.5
作者：
Gkountela S;Zhang KX;Shafiq TA;Liao WW;Hargan-Calvopiña J;Chen PY;Clark AT
通讯作者：
Clark AT
影响因子：
11.8
作者：
Dawlaty, Meelad M.;Breiling, Achim;Le, Thuc;Raddatz, Guenter;Barrasa, M. Inmaculada;Cheng, Albert W.;Gao, Qing;Powell, Benjamin E.;Li, Zhe;Xu, Mingjiang;Faull, Kym F.;Lyko, Frank;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf