A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development.
A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development.
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DOI：
10.1016/j.cell.2015.04.053
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发表时间：
2015-06-04
期刊：
影响因子：
64.5
通讯作者：
Surani MA
中科院分区：
文献类型：
--
作者：
Tang WW;Dietmann S;Irie N;Leitch HG;Floros VI;Bradshaw CR;Hackett JA;Chinnery PF;Surani MA
重置人类原始生殖细胞（hPGC）中的表观基因组对发育至关重要。我们发现，hPGC的转录程序是不同的，在小鼠中，与体细胞的指定和幼稚的多能性基因TFCP 2L 1和KLF 4的共表达。这种由SOX 17和BLIMP 1建立的独特基因调控网络通过抑制DNA甲基化途径和激活TET介导的羟甲基化来驱动全面的种系DNA去甲基化。碱基分辨率甲基化组分析揭示了在体内hPGC中第5-7周进行性DNA去甲基化至基础水平。同时，hPGC经历染色质重组、X再活化和印记擦除。尽管全球低甲基化，进化年轻和潜在的危险retroelements，如SVA，保持甲基化。值得注意的是，一些与代谢和神经系统疾病相关的基因座也对DNA去甲基化具有抗性，揭示了可能具有表型后果的跨代表观遗传的潜力。我们提供了对早期人类生殖系转录网络和表观遗传重编程的全面见解，这些转录网络和表观遗传重编程随后影响人类发育和疾病。SOX 17-BLIMP 1与TFCP 2L 1和KLF 4构成独特的hPGC转录组hPGC转录组驱动广泛的DNA去甲基化和染色质重组进化上年轻和危险的逆转录转座子保持部分甲基化一些去甲基化抗性基因座是表观遗传的候选基因独特的转录组驱动人类原始生殖细胞中广泛的表观基因组重置以建立全能性。一些与代谢和神经系统疾病相关的基因座表现出对重编程的抗性，并且是跨代表观遗传的候选者。
Resetting of the epigenome in human primordial germ cells (hPGCs) is critical for development. We show that the transcriptional program of hPGCs is distinct from that in mice, with co-expression of somatic specifiers and naive pluripotency genes TFCP2L1 and KLF4. This unique gene regulatory network, established by SOX17 and BLIMP1, drives comprehensive germline DNA demethylation by repressing DNA methylation pathways and activating TET-mediated hydroxymethylation. Base-resolution methylome analysis reveals progressive DNA demethylation to basal levels in week 5–7 in vivo hPGCs. Concurrently, hPGCs undergo chromatin reorganization, X reactivation, and imprint erasure. Despite global hypomethylation, evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated. Remarkably, some loci associated with metabolic and neurological disorders are also resistant to DNA demethylation, revealing potential for transgenerational epigenetic inheritance that may have phenotypic consequences. We provide comprehensive insight on early human germline transcriptional network and epigenetic reprogramming that subsequently impacts human development and disease. SOX17-BLIMP1 with TFCP2L1 and KLF4 constitute a unique hPGC transcriptome hPGC transcriptome drives extensive DNA demethylation and chromatin reorganization Evolutionarily young and hazardous retrotransposons remain partially methylated Some demethylation resistant loci are candidates for epigenetic inheritance A unique transcriptome drives extensive epigenome resetting in human primordial germ cells for establishment of totipotency. Some loci associated with metabolic and neurological disorders exhibit resistance to reprogramming and are candidates for transgenerational epigenetic inheritance.
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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：
64.8
作者：
Jacobs, Frank M. J.;Greenberg, David;Ngan Nguyen;Haeussler, Maximilian;Ewing, Adam D.;Katzman, Sol;Paten, Benedict;Salama, Sofie R.;Haussler, David
通讯作者：
Haussler, David
影响因子：
4
作者：
Hancks, Dustin C.;Kazazian, Haig H., Jr.
通讯作者：
Kazazian, Haig H., Jr.
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
早期人类发育过程中DNA甲基化动力学的全基因组分析。
影响因子：
4.5
作者：
Okae H;Chiba H;Hiura H;Hamada H;Sato A;Utsunomiya T;Kikuchi H;Yoshida H;Tanaka A;Suyama M;Arima T
通讯作者：
Arima T