化学特征揭示基因组的遗传开关

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在基因组的茫茫核苷酸序列中找到基因(即“什么”)已实属不易，但是即便找到了，摆在科学家们面前的还有很多更为重要的问题等待他们解决——基因产物“为什么”、“什么时间”和“什么地点”表达。现在，LICR研究小组的成员开发了一套新的方案，可以用它来识别和预测调控基因转录的核苷酸区域，包括“启动子”和“增强子”。

  “人类基因组是包裹在染色质当中的，确切地说是由组蛋白包裹DNA，”文章第一作者Nathaniel Heintzman介绍说，“针对全基因组序列，我们分析了人类细胞的染色质结构，发现一些已知启动子、增强子附近的经修饰的组蛋白都有一些独特的记号。根据这些特征，我们采用一些计算机上的算法识别出了好几百个具有潜在调控功能的基因组区域。”此外，Heintzman补充道，这种“组蛋白密码”可以准确地分辨启动子和增强子序列。

  研究的通讯作者Bing Ren是UCSD（**）细胞和分子医学系的副教授，他认为这种方法的理论具有普遍性，而且可以运用这套相对公正的方法探索基因表达在患病情况下是如何变化的分子机制。“这个方法的魅力所在是它依赖于组蛋白的化学特征，而不是DNA的。现在常用来预测增强子的方法完全依赖于DNA序列，这种方法是不可靠的，因为我们对增强子的特征还没有完全弄清。对于组蛋白修饰特征的解析将让科学家快速识别出基因的增强子和启动子，在此基础上可以进一步方便快捷地识别调控基因表达的因子。”这种方法还可以用来识别在癌症发生过程中基因网络异常的发生，这将推动癌症检测技术的开发，Ren最后补充道。


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 biren@ucsd.edu

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