日本研究人員稱,，他們解開了被稱為“跳躍基因”的轉(zhuǎn)位子在胚胎干細(xì)胞中受到抑制的詳細(xì)機(jī)理。這項(xiàng)成果有望廣泛應(yīng)用于誘導(dǎo)多能干細(xì)胞（iPS細(xì)胞）和基因載體的研究,。
轉(zhuǎn)位子是具有特定功能的基因片段,，它可以自我復(fù)制并在基因序列中四處移動(dòng)。一些轉(zhuǎn)位子有調(diào)控基因表達(dá)的作用,，可誘發(fā)基因突變,。因此，生物體內(nèi)存在抑制轉(zhuǎn)位子的機(jī)制,。通常,，這種抑制是通過DNA甲基化來實(shí)現(xiàn)的。而在胚胎干細(xì)胞中,，人們已經(jīng)發(fā)現(xiàn)存在DNA甲基化以外的抑制機(jī)理,，但詳細(xì)情況一直未得到解釋。
日本京都大學(xué)病毒研究所教授真貝洋一等研究人員在利用實(shí)驗(yàn)鼠的胚胎干細(xì)胞進(jìn)行實(shí)驗(yàn)時(shí)發(fā)現(xiàn),，如果阻止一種酶“ESET”發(fā)揮作用,，那么轉(zhuǎn)位子的一種、內(nèi)源性逆轉(zhuǎn)錄病毒在細(xì)胞內(nèi)就會(huì)變得異?；钴S,。與“ESET”正常發(fā)揮作用時(shí)相比，病毒數(shù)量增加到25倍,。這說明,，“ESET”是控制轉(zhuǎn)位子活躍程度的一種“開關(guān)”,。
在iPS細(xì)胞和基因載體等的研究中，控制特定基因發(fā)揮作用是一項(xiàng)非常重要的技術(shù),。研究人員表示,，這項(xiàng)成果有望廣泛應(yīng)用于iPS細(xì)胞和基因載體的研究中。（生物谷Bioon.com）
生物谷推薦原文閱讀：
Nature advance online publication 17 February 2010 | doi:10.1038/nature08858
Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET
Toshiyuki Matsui1,2,5, Danny Leung3,5, Hiroki Miyashita1,2, Irina A. Maksakova3, Hitoshi Miyachi1, Hiroshi Kimura4, Makoto Tachibana1,2, Matthew C. Lorincz3 & Yoichi Shinkai1,2
Experimental Research Center for Infectious Diseases, Institute for Virus Research, and,
Graduate School of Biostudies, Kyoto University, 53 Shogoin, Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Department of Medical Genetics, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan
These authors contributed equally to this work.
Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising ~10% of the mouse genome1. These parasitic elements are responsible for >10% of spontaneous mutations2. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells3, 4, 5, an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV)6, 7, 8. Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts9. However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Krüppel-associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28)10, 11 are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (Dnmt1 -/- Dnmt3a -/- Dnmt3b -/-) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.
