Nature：对胚胎发育重要的蛋白质复合体(转帖）

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虽然每个细胞所含的DNA是相同的，但每个细胞的分化命运却不尽相同。干细胞的最终分化命运不仅与DNA有关，还与覆盖在DNA结构上的表观遗传标记物有关。# ^7 F4 r% |' Y; u# N
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最近，UNC医学院的研究人员发现了一种蛋白质复合体——延伸因子(elongator)，这种蛋白质复合体能够清除精子DNA上的表观遗传标记物，对胚胎发育过程形成不同类型的细胞有重要的作用。这种延伸因子或许还可通过清除表观遗传标记的方式再次激活肿瘤抑制基因，从而使肿瘤细胞转化为正常细胞。这项研究发表在1月6日Nature杂志上。- p# |. i6 m$ L$ n) j: Z$ Q! z- r
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表观遗传标记物是一种标记在基因组上的化学标签，能够调控基因的开启和关闭，并最终决定细胞分化的类型。DNA甲基化即为表观遗传标记物的一种类型。4 ^( z; o! I' M" O: |
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在受精过程中，父系的精子的基因组发生去甲基化，在细胞分裂之前迅速去掉甲基标签，而母系的卵子在这种情况下也发生被动地发生去甲基化。随后，受精卵重新形成一种全新的甲基化模式。( @7 O# W5 Q* Q9 A
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该课题组通过使绿色荧光标记物亲和连接到非甲基化DNA上，能够在显微镜下观察到整个去甲基化的过程。研究人员敲除掉受精卵中延伸因子基因后发现，荧光标签将不能连接到亲代的基因组中，这说明，延伸因子对去甲基化(demethylation)很重要。
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研究人员称，该基因的识别或将对干细胞研究十分重要。（生物谷Bioon.com）
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/ q0 H& z$ V$ ^( ^6 BNature 6 January 2010 | doi:10.1038/nature08732
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  N7 @6 Q, w8 X% H' I; JA role for the elongator complex in zygotic paternal genome demethylation7 u6 m0 A! c+ e' p- e& D
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Yuki Okada1,2,4, Kazuo Yamagata3, Kwonho Hong1,2, Teruhiko Wakayama3 & Yi Zhang1,2
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1 Howard Hughes Medical Institute,
: e+ A, {& ^3 ~8 k2 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA1 E& @: S- g2 e; [! w" ^# q
3 Laboratory for Genomic Reprogramming, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan* T5 o! u$ m. {6 U: M5 B9 \
4 Present address: Career-Path Promotion Unit for Young Life Scientist, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
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The life cycle of mammals begins when a sperm enters an egg. Immediately after fertilization, both the maternal and paternal genomes undergo dramatic reprogramming to prepare for the transition from germ cell to somatic cell transcription programs1. One of the molecular events that takes place during this transition is the demethylation of the paternal genome2, 3. Despite extensive efforts, the factors responsible for paternal DNA demethylation have not been identified4. To search for such factors, we developed a live cell imaging system that allows us to monitor the paternal DNA methylation state in zygotes. Through short-interfering-RNA-mediated knockdown in mouse zygotes, we identified Elp3 (also called KAT9), a component of the elongator complex5, to be important for paternal DNA demethylation. We demonstrate that knockdown of Elp3 impairs paternal DNA demethylation as indicated by reporter binding, immunostaining and bisulphite sequencing. Similar results were also obtained when other elongator components, Elp1 and Elp4, were knocked down. Importantly, injection of messenger RNA encoding the Elp3 radical SAM domain mutant, but not the HAT domain mutant, into MII oocytes before fertilization also impaired paternal DNA demethylation, indicating that the SAM radical domain is involved in the demethylation process. Our study not only establishes a critical role for the elongator complex in zygotic paternal genome demethylation, but also indicates that the demethylation process may be mediated through a reaction that requires an intact radical SAM domain.

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