Role of Tet1 in erasure of genomic imprinting.
Role of Tet1 in erasure of genomic imprinting.
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基因组印迹是一种对哺乳动物发育和功能具有重要意义的等位基因特异性基因表达系统。基因组印迹的分子基础是等位基因特异性DNA甲基化。虽然我们都知道从头开始的DNA甲基转移酶Dnmt3a/b负责基因组印迹的建立，但甲基化标记如何在原始生殖细胞（PGC）重编程过程中被擦除仍然是一个谜。Tet1是10 - 11易位家族蛋白之一，具有氧化5-甲基胞嘧啶（5mC）的能力，在重编程PGCs中特异性表达。在这里，我们报告了Tet1在基因组印迹的消除中起着关键作用。我们发现，尽管Tet1-KO雄性和野生型雌性交配产生的后代具有相同的基因型，但它们表现出许多不同的表型，包括胎盘、胎儿和产后生长缺陷以及早期胚胎致命性。这些缺陷至少部分是由印迹基因的失调引起的，如Peg10和Peg3，它们在差异甲基化区（DMRs）的父本等位基因中表现出异常的高甲基化。RNA-seq揭示了由于父本Tet1功能缺失导致下一代印迹基因的广泛失调。对Tet1-KO小鼠的E13.5 PGCs和精子进行全基因组DNA甲基化分析，发现精子中印迹基因DMRs的高甲基化可追溯到PGCs。对重编程PGCs中DNA甲基化动力学的分析表明，在重编程后期，Tet1的功能是清除剩余的甲基化，包括印迹基因。我们进一步提供证据支持Tet1在消除雌性种系父系印记中的作用。因此，我们的研究确定了Tet1在基因组印迹消除中的关键功能。
Genomic imprinting is an allele-specific gene expression system important for mammalian development and function . The molecular basis of genomic imprinting is allele-specific DNA methylation . While it is well known that the de novo DNA methyltransferases Dnmt3a/b are responsible for the establishment of genomic imprinting , how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains a mystery. Tet1 is one of the ten-eleven translocation family proteins, which have the capacity to oxidize 5-methylcytosine (5mC) , specifically expressed in reprogramming PGCs . Here we report that Tet1 plays a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1-KO males and wild-type females exhibit a number of variable phenotypes including placental, fetal and postnatal growth defects, and early embryonic lethality. These defects are, at least in part, caused by the dysregulation of imprinted genes, such as Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal loss function of Tet1. Genome-wide DNA methylation analysis of E13.5 PGCs and sperms of Tet1-KO mice revealed hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Analysis of the DNA methylation dynamics in reprogramming PGCs suggests that Tet1 functions to wipe out remaining methylation, including imprinted genes, at the late reprogramming stage. We further provide evidence supporting Tet1's role in the erasure of paternal imprints in female germline. Thus, our study establishes a critical function of Tet1 in genomic imprinting erasure.
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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：
16
作者：
Piccolo, Francesco M.;Bagci, Hakan;Brown, Karen E.;Landeira, David;Soza-Ried, Jorge;Feytout, Amelie;Mooijman, Dylan;Hajkova, Petra;Leitch, Harry G.;Tada, Takashi;Kriaucionis, Skirmantas;Dawlaty, Meelad M.;Jaenisch, Rudolf;Merkenschlager, Matthias;Fisher, Amanda G.
通讯作者：
Fisher, Amanda G.
影响因子：
14.9
作者：
Blake JA;Bult CJ;Eppig JT;Kadin JA;Richardson JE;Mouse Genome Database Group
通讯作者：
Mouse Genome Database Group
影响因子：
1.7
作者：
Kobayashi, H.;Suda, C.;Sasaki, H.
通讯作者：
Sasaki, H.
影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf