生物谷報(bào)道：來自丹麥哥本哈根大學(xué)的研究人員確定出一個(gè)對(duì)胚胎發(fā)育至關(guān)重要的新基因家族——UTX-JMJD3,。這個(gè)家族控制對(duì)干細(xì)胞維持和分化很關(guān)鍵的基因的表達(dá)。這項(xiàng)新發(fā)現(xiàn)可能有助于促進(jìn)人們對(duì)癌癥形成的了解,。
這項(xiàng)研究的結(jié)果發(fā)表在最新一期的《自然》雜志上,，這篇文章是該研究組繼去年發(fā)表在《自然》和Cell雜志的兩篇文章的后續(xù),。
胚胎干細(xì)胞如何產(chǎn)生由不同類型細(xì)胞構(gòu)成的生物體？而且每種細(xì)胞都可制造不同的蛋白質(zhì),。神經(jīng)細(xì)胞禪師神經(jīng)細(xì)胞功能所需的蛋白質(zhì),；肌肉細(xì)胞產(chǎn)生肌肉功能所需的蛋白質(zhì)等等。所有這些特化的細(xì)胞都起源于同一個(gè)類型的細(xì)胞——胚胎干細(xì)胞,。在高度控制的分化過程中,，干細(xì)胞被誘導(dǎo)變成特化細(xì)胞。
基因家族幫助調(diào)節(jié)干細(xì)胞分化,。丹麥的這些研究人員確定出了一種新的基因家族,，這個(gè)家族能夠修飾對(duì)分化調(diào)節(jié)過程很關(guān)鍵的基因表達(dá)。研究人員通過使用人類和小鼠干細(xì)胞進(jìn)行研究,，從而獲得了這些結(jié)果,。此外，他們還研究了線蟲的發(fā)育,。
基因家族是指由一個(gè)祖先基因經(jīng)重復(fù)和變異（見第25章）所產(chǎn)生的一組同源基因,，稱基因家族。不同的基因家族其成員的多少（表10-6）結(jié)構(gòu)和功能的相似性都不相同,，分散的基因家族其成員員不在同一基因簇內(nèi),，至少不在同一染色體上，串聯(lián)基因家族的成員都集中串聯(lián)在一起,。有的基因家族成員具有和原有基因相同的結(jié)構(gòu)和功能,，如小鼠珠蛋基因家族有5個(gè)基因，一個(gè)是胚胎型的（α-emx）,，另兩個(gè)是成體型的（α-ad1 和α-ad2）,，它們都在第11號(hào)染色體上，這三個(gè)基因都可以編碼,，α-ad1 和α-ad2所編碼的蛋白質(zhì)僅在第68位上的氨基酸不同,。
2005年，美國天普大學(xué)（Temple University）斯巴洛癌癥及分子醫(yī)學(xué)研究所的研究人員發(fā)現(xiàn)的一個(gè)叫做新穎結(jié)構(gòu)蛋白（NSP）的新基因家族可能成為一種預(yù)測病人腫瘤生長風(fēng)險(xiǎn)的標(biāo)記,。這項(xiàng)研究的相關(guān)文章刊登在Oncogene雜志上,。
研究人員成功克隆出了幾種相互聯(lián)系但又各不相同的cDNA，這些cDNA編碼新穎結(jié)構(gòu)蛋白,?？寺》治霰砻鬟@些基因很獨(dú)特并且它們的主要結(jié)構(gòu)部分編碼人類染色體的一個(gè)區(qū)域，這個(gè)區(qū)域?qū)θ旧w結(jié)構(gòu)的維持非常重要,。因此,，研究人員推測這種基因可能對(duì)控制細(xì)胞的骨架非常重要。
研究人員最初的分析表明這個(gè)基因家族通常位于細(xì)胞核中并且表現(xiàn)出腫瘤促進(jìn)基因的特征,。這個(gè)基因的一種形式（NSP5a3a）在一些腫瘤細(xì)胞株中的表達(dá)水平很高,，因此它或許能充當(dāng)一種腫瘤標(biāo)記,。
知道了這個(gè)基因家族的遺傳情形以及NSP變異影響遺傳狀況的機(jī)制就可能使這個(gè)家族成為腫瘤惡化的一個(gè)強(qiáng)有力的指示器。人們也可以通過分析這種基因來預(yù)測腫瘤生長的可能性,。
原始出處:
Nature advance online publication 22 August 2007 | doi:10.1038/nature06145; Received 2 July 2007; Accepted 3 August 2007; Published online 22 August 2007
UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development
Karl Agger1,2,5, Paul A. C. Cloos1,2,5, Jesper Christensen1,2,5, Diego Pasini1,2, Simon Rose1, Juri Rappsilber3, Irina Issaeva4, Eli Canaani4, Anna Elisabetta Salcini1 & Kristian Helin1,2
Biotech Research and Innovation Centre (BRIC), and,
Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
These authors contributed equally to this work.
Correspondence to: Kristian Helin1,2 Correspondence and requests for materials should be addressed to K.H. (Email: [email protected]).
The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates1, 2, 3. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3)3. Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells4, 5, 6, 7. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.
