Charting a dynamic DNA methylation landscape of the human genome.
Charting a dynamic DNA methylation landscape of the human genome.
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作者：
DNA甲基化是哺乳动物细胞身份的一个决定性特征，对正常发育至关重要。大多数细胞类型，除了生殖细胞和植入前胚胎，显示出相对稳定的DNA甲基化模式，70-80%的CpGs被甲基化。尽管最近取得了一些进展，但我们对何时、何地以及有多少CpGs参与基因组调控的理解仍然非常有限。在这里，我们报告了对30种不同人类细胞和组织类型的42个全基因组亚硫酸盐测序（WGBS）数据集的深入分析。我们观察到在正常发育背景下，只有21.8%的常染色体CpGs有动态调控，其中大多数位于转录起始位点的远端。这些动态CpGs与基因调控元件共定位，特别是增强子和转录因子结合位点（TFBS），这使得鉴定关键谱系特异性调控因子成为可能。此外，差异甲基化区域（DMRs）通常含有与GWAS确定的细胞类型相关疾病相关的snp。结果还强调了WGBS的普遍低效率，因为在这些数据集中，70-80%的测序读取很少或没有提供关于CpG甲基化的相关信息。为了进一步证明我们的DMR集的实用性，我们使用它对未知样本进行分类，并识别概括主要DNA甲基化动力学的代表性特征区域。总之，尽管理论上每个CpG都可以改变其甲基化状态，但我们的研究结果表明，只有一小部分CpG可以作为协调调节程序的一部分改变甲基化状态。因此，我们选择的DMRs可以作为一个起点，帮助指导新的、更有效的简化表示方法，以捕获cpg的最具信息量的部分，并进一步确定假定的调控元件。
DNA methylation is a defining feature of mammalian cellular identity and essential for normal development. Most cell types, except germ cells and pre-implantation embryos, display relatively stable DNA methylation patterns with 70–80% of all CpGs being methylated. Despite recent advances we still have a too limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in depth analysis of 42 whole genome bisulfite sequencing (WGBS) data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, a majority of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription factor binding sites (TFBS), which allow identification of key lineage specific regulators. In addition, differentially methylated regions (DMRs) often harbor SNPs associated with cell type related diseases as determined by GWAS. The results also highlight the general inefficiency of WGBS as 70–80% of the sequencing reads across these data sets provided little or no relevant information regarding CpG methylation. To further demonstrate the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore our selected DMRs can serve as a starting point to help guide novel, more effective reduced representation approaches to capture the most informative fraction of CpGs as well as further pinpoint putative regulatory elements.
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影响因子：
3.8
作者：
Dedeurwaerder, Sarah;Defrance, Matthieu;Fuks, Francois
通讯作者：
Fuks, Francois
DOI：
10.1126/science.1222794
发表时间：
2012-09-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maurano MT;Humbert R;Rynes E;Thurman RE;Haugen E;Wang H;Reynolds AP;Sandstrom R;Qu H;Brody J;Shafer A;Neri F;Lee K;Kutyavin T;Stehling-Sun S;Johnson AK;Canfield TK;Giste E;Diegel M;Bates D;Hansen RS;Neph S;Sabo PJ;Heimfeld S;Raubitschek A;Ziegler S;Cotsapas C;Sotoodehnia N;Glass I;Sunyaev SR;Kaul R;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
影响因子：
7
作者：
Li, Heng;Ruan, Jue;Durbin, Richard
通讯作者：
Durbin, Richard
DOI：
10.1073/pnas.0903103106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Hindorff, Lucia A.;Sethupathy, Praveen;Manolio, Teri A.
通讯作者：
Manolio, Teri A.
影响因子：
46.9
作者：
Gnirke A;Melnikov A;Maguire J;Rogov P;LeProust EM;Brockman W;Fennell T;Giannoukos G;Fisher S;Russ C;Gabriel S;Jaffe DB;Lander ES;Nusbaum C
通讯作者：
Nusbaum C