加州大學(xué)路德維格癌癥研究所(*)的研究者在人類基因組中發(fā)現(xiàn)了一個(gè)功能性元件,，一篇最新報(bào)道的《Nature Genetics》研究性文章稱,。
在基因組的茫茫核苷酸序列中找到基因(即“什么”)已實(shí)屬不易，但是即便找到了,，擺在科學(xué)家們面前的還有很多更為重要的問題等待他們解決——基因產(chǎn)物“為什么”,、“什么時(shí)間”和“什么地點(diǎn)”表達(dá)。現(xiàn)在,，LICR研究小組的成員開發(fā)了一套新的方案,，可以用它來識(shí)別和預(yù)測調(diào)控基因轉(zhuǎn)錄的核苷酸區(qū)域，包括“啟動(dòng)子”和“增強(qiáng)子”,。
“人類基因組是包裹在染色質(zhì)當(dāng)中的,，確切地說是由組蛋白包裹DNA，”文章第一作者Nathaniel Heintzman介紹說，“針對(duì)全基因組序列,，我們分析了人類細(xì)胞的染色質(zhì)結(jié)構(gòu),，發(fā)現(xiàn)一些已知啟動(dòng)子、增強(qiáng)子附近的經(jīng)修飾的組蛋白都有一些獨(dú)特的記號(hào),。根據(jù)這些特征,，我們采用一些計(jì)算機(jī)上的算法識(shí)別出了好幾百個(gè)具有潛在調(diào)控功能的基因組區(qū)域。”此外,，Heintzman補(bǔ)充道，這種“組蛋白密碼”可以準(zhǔn)確地分辨啟動(dòng)子和增強(qiáng)子序列,。
研究的通訊作者Bing Ren是UCSD（**）細(xì)胞和分子醫(yī)學(xué)系的副教授,，他認(rèn)為這種方法的理論具有普遍性，而且可以運(yùn)用這套相對(duì)公正的方法探索基因表達(dá)在患病情況下是如何變化的分子機(jī)制,。“這個(gè)方法的魅力所在是它依賴于組蛋白的化學(xué)特征,，而不是DNA的。現(xiàn)在常用來預(yù)測增強(qiáng)子的方法完全依賴于DNA序列,，這種方法是不可靠的,，因?yàn)槲覀儗?duì)增強(qiáng)子的特征還沒有完全弄清。對(duì)于組蛋白修飾特征的解析將讓科學(xué)家快速識(shí)別出基因的增強(qiáng)子和啟動(dòng)子,，在此基礎(chǔ)上可以進(jìn)一步方便快捷地識(shí)別調(diào)控基因表達(dá)的因子,。”這種方法還可以用來識(shí)別在癌癥發(fā)生過程中基因網(wǎng)絡(luò)異常的發(fā)生，這將推動(dòng)癌癥檢測技術(shù)的開發(fā),，Ren最后補(bǔ)充道,。
英文摘要：
Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome
Nathaniel D Heintzman1, 2, Rhona K Stuart1, Gary Hon1, 3, Yutao Fu4, Christina W Ching1, R David Hawkins1, Leah O Barrera1, 3, Sara Van Calcar1, Chunxu Qu1, Keith A Ching1, Wei Wang5, Zhiping Weng4, 6, Roland D Green7, Gregory E Crawford8 & Bing Ren1, 9
1 Ludwig Institute for Cancer Research, University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653 USA.
2 Biomedical Sciences Graduate Program, University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653 USA.
3 Program in Bioinformatics and University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653 USA.
4 Bioinformatics Program, Boston University, 24 Cummington Street, 1002, Boston, Massachusetts 02215 USA.
5 Department of Chemistry and Biochemistry, UCSD, 9500 Gilman Drive, La Jolla, California 92093 USA.
6 Biomedical Engineering Department, Boston University, 44 Cummington Street, Boston, MA 02215.
7 NimbleGen Systems, Inc., 1 Science Court, Madison, Wisconsin 53711 USA.
8 Institute for Genome Sciences & Policy and Department of Pediatrics, Duke University, 101 Science Drive, Durham, North Carolina 27708, USA.
9 Department of Cellular and Molecular Medicine, University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653 USA.
Correspondence should be addressed to Bing Ren [email protected]
Eukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of Lys4 of histone H3 (H3K4), whereas enhancers are marked by monomethylation, but not trimethylation, of H3K4. We developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). Our results give insight into the connections between chromatin modifications and transcriptional regulatory activity and provide a new tool for the functional annotation of the human genome.
英文原文鏈接：http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng1966.html
