Nature重要发现：基因组印记的“擦除器”

　　

生物通报道  来自波士顿儿童医院的研究人员在一项新研究中揭示，一种叫做Tet1的蛋白在原始生殖细胞发育为精子和卵细胞之前清理了它们的表观遗传记录。这一研究发现有可能帮助提供一些关于某些新生儿生长缺陷病因的线索，或许还可帮助推动开发出疾病的干细胞模型。

这一研究小组由波士顿儿童医院细胞和分子医学项目张毅（Yi Zhang）博士和Shinpei Yamaguchi博士共同领导。研究结果发表在12月1日的《自然》（Nature）杂志上。

我们基因组中的所有基因在我们的每一个细胞中都具有两个拷贝，称之为等位基因，每个拷贝分别来自于我们的父母。某些基因的一个等位基因被打上印记（用称作为甲基的小化学标签标记）使其保持沉默状态，防止两个拷贝之间发生生物冲突。

在原始生殖细胞长成精子或卵细胞之前，它的印记模式被擦除，随后以一种等位基因特异性的方式重建。这一过程确保了在发育胚胎中每对等位基因只有一个得以表达。

张毅和Yamaguchi在缺失Tet1基因的小鼠模型中证实，缺失Tet1蛋白阻止了原始生殖细胞清除它们的印记，导致了胚胎致死以及活产后代的体积变小。这些结果表明，Tet1突变有可能促成了某些人类出生缺陷，并提供了这一擦除过程潜在机制的一些新认识。

张毅说：“很早以前我们就知道哪些蛋白负责建立印记模式，但对于擦除过程的发生机制却不是很清楚。”

“我们发现，Tet1并非单独行动擦除了基因组印记，但它是一个重要的因子。我们需要开展更多的研究工作来了解其他与之相关的蛋白。”

张毅指出，适当的印记也在细胞重编程，例如诱导多能干(iPS)细胞生成中起作用。

他说：“正确的印记模式对于维持正常的发育和分化至关重要，但我们常在重编程后的iPS细胞中观察到异常的印记模式。了解印记的擦除机制，有可能促成更有效的方法来生成高质量的iPS细胞。”

（生物通：何嫱）

生物通推荐原文摘要：

Role of Tet1 in erasure of genomic imprinting

Genomic imprinting is an allele-specific gene expression system that is important for mammalian development and function1. The molecular basis of genomic imprinting is allele-specific DNA methylation1, 2. Although it is well known that the de novo DNA methyltransferases Dnmt3a and Dnmt3b are responsible for the establishment of genomic imprinting3, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains unclear. Tet1 is one of the ten-eleven translocation family proteins, which have the capacity to oxidize 5-methylcytosine (5mC)4, 5, 6, specifically expressed in reprogramming PGCs7. Here we report that Tet1 has a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1 knockout males and wild-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 of Tet1 function. Genome-wide DNA methylation analysis of embryonic day 13.5 PGCs and sperm of Tet1 knockout 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 indicates that Tet1 functions to wipe out remaining methylation, including imprinted genes, at the late reprogramming stage. Furthermore, we provide evidence supporting the role of Tet1 in the erasure of paternal imprints in the female germ line. Thus, our study establishes a critical function of Tet1 in the erasure of genomic imprinting.