近日,，IBM公司和新加坡基因組研究所（Genome Institute of Singapore）合作在Nature發(fā)表有關(guān)microRNA控制干細(xì)胞分化的機(jī)制的研究論文,。
來(lái)自IBM和GIS兩組團(tuán)隊(duì)研究得出共識(shí),，microRNA調(diào)節(jié)活細(xì)胞的能力比先前所預(yù)先的要強(qiáng)很多,，microRNA是一類(lèi)小分子RNA,，是調(diào)節(jié)活細(xì)胞功能的重要因子。近年來(lái),，microRNA成為科學(xué)家們熱捧的研究對(duì)象,。
在2006年，IBM的科學(xué)家就構(gòu)建了一種數(shù)學(xué)模型,，用于預(yù)測(cè)microRNA的功能,。研究小組為了檢驗(yàn)數(shù)學(xué)模型的可靠性，在小鼠干細(xì)胞中進(jìn)行實(shí)踐,。IBM公司通過(guò)數(shù)據(jù)分析的電腦,，而新加坡基因組研究所的科學(xué)家對(duì)上述模型進(jìn)行實(shí)體檢驗(yàn)。
兩隊(duì)研究小組共同的目標(biāo)是研究microRNA指導(dǎo)干細(xì)胞分化調(diào)節(jié)的機(jī)制,，尤其是某些影響人類(lèi)健康的重大疾病的干細(xì)胞分化的microRNA調(diào)節(jié)機(jī)制,， 比如說(shuō)，癌癥,、神經(jīng)變性疾病,、糖尿病和其他疾病。研究小組希望有朝一日這些研究成果都可以用于指導(dǎo)疾病的診斷和治療,。
IBM計(jì)算生物學(xué)中心的生物信息學(xué)主管Isidore Rigoutsos說(shuō),，我們的計(jì)劃是了解microRNAs調(diào)節(jié)細(xì)胞功能的復(fù)雜機(jī)制。我們發(fā)現(xiàn)microRNAs調(diào)節(jié)的靶位在轉(zhuǎn)錄的氨基酸上,，這一發(fā)現(xiàn)令人十分興奮,。
新加坡基因組研究所研究小組的高級(jí)主管Bing Lim補(bǔ)充到，我們從實(shí)驗(yàn)中了解到以microRNAs定向以編碼區(qū)為靶位對(duì)細(xì)胞具有深刻的調(diào)節(jié)作用,。我們觀察到單個(gè)的microRNA序列對(duì)胚胎干細(xì)胞的分化具有強(qiáng)大的調(diào)控能力,。這一結(jié)果令人十分興奮，我們可以用microRNA分子來(lái)控制干細(xì)胞的分化,，或是制備新的干細(xì)胞,。最有趣的是，研究者可通過(guò)計(jì)算機(jī)預(yù)測(cè)觀察細(xì)胞分化的過(guò)程,。
具體成果細(xì)節(jié)
在近十年來(lái),，microRNA研究人員最初認(rèn)為microRNA通過(guò)3''端非翻譯區(qū)（3'UTR）與mRNA相互作用。
研究人員認(rèn)為,，microRNA作用的靶位相對(duì)保守,，不同的有機(jī)體作用的mRNA區(qū)域相似，而與3'UTR的作用是非典型的作用模式,。
但是,，最新的一些研究發(fā)現(xiàn)，microRNA的作用靶位不僅是mRNA的非編碼區(qū),，microRNA還能與mRNA的編碼區(qū)作用,，相關(guān)的研究結(jié)果,，兩研究小組發(fā)表在早期的期刊上。這也就表明,，mRNA編碼區(qū)受microRNA調(diào)控,，蛋白翻譯過(guò)程也受microRNA調(diào)控。
研究小組發(fā)現(xiàn),，小鼠胚胎干細(xì)胞分化的過(guò)程中,，三種獨(dú)特的microRNA的表達(dá)量顯著升高，Nanog,，Oct4和Sox2這三個(gè)轉(zhuǎn)錄子對(duì)小鼠胚胎干細(xì)胞的多能性的維持具有重要的意義,，并且是控制胚胎干細(xì)胞初始分化的因子，這三個(gè)microRNA通過(guò)mRNA的編碼區(qū)來(lái)起調(diào)節(jié)作用,。研究人員通過(guò)下調(diào)轉(zhuǎn)錄因子可阻止干細(xì)胞分化,。
研究人員發(fā)現(xiàn)三個(gè)microRNA在獼猴和小鼠的作用靶位并不相同，這就說(shuō)明這些作用靶序列并不保守,。這一結(jié)果表明,，通過(guò)不同的有機(jī)體來(lái)預(yù)測(cè)microRNA的作用靶位并不可靠，因?yàn)檎嬲膍icroRNA靶位并不保守,。
此外,，研究小組還發(fā)現(xiàn)，一個(gè)microRNA具有多個(gè)mRNA編碼區(qū)作用靶位,，對(duì)不同的基因都具有作用力,，這是機(jī)體確保調(diào)節(jié)功能奏效的機(jī)制。microRNA在基因的剪切體上具有多重作用,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature (17 Sep 2008), doi: 10.1038/nature07299, Letters to Editor
MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation
Yvonne Tay1,4, Jinqiu Zhang1, Andrew M. Thomson1,5, Bing Lim1,2,5 & Isidore Rigoutsos3,5
1. Stem Cell and Developmental Biology, Genome Institute of Singapore, Agency for Science Technology and Research (A*STAR), #08-01, Genome, 60 Biopolis Street, Singapore 138672, Singapore
2. Beth-Israel Medical Center, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02215, USA
3. Bioinformatics and Pattern Discovery Group, IBM Thomas J. Watson Research Center, Yorktown Heights, PO Box 218, New York 10598, USA
4. Present address: Experimental Therapeutics Center, Agency for Science Technology and Research (A*STAR), Nanos Level 3, 31 Biopolis Way, Singapore 138669, Singapore.
5. These authors contributed equally to this work.
MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner1, 2, 3, 4, 5, 6,7. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3' untranslated regions of mRNAs1, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes8, 9, 10, 11 and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon–exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3' untranslated region.
