De novo DNA demethylation and noncoding transcription define active intergenic regulatory elements.
De novo DNA demethylation and noncoding transcription define active intergenic regulatory elements.
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DOI：
10.1101/gr.157271.113
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发表时间：
2013-10
期刊：
影响因子：
7
通讯作者：
Hodges E
中科院分区：
文献类型：
--
作者：
Schlesinger F;Smith AD;Gingeras TR;Hannon GJ;Hodges E
哺乳动物DNA甲基化组的深度测序揭示了基因间空间（iHMR）中先前未预测的离散低甲基化区域的数量。在这里，我们结合了全基因组亚硫酸氢盐测序数据与广泛的基因表达和染色质状态数据来定义iHMR的功能类别，并重建其在发育环境中建立的动态。比较胚胎干细胞和原代血细胞中的HMR谱，我们发现iHMR标记活性DNA酶超敏位点（DHS）的一个独有子集，并且发育组成性和细胞类型特异性iHMR都显示典型的不同调控元件的染色质状态。我们还观察到iHMR的变化比启动子HMR本身更能预测附近基因的活性，并且iHMR内非编码RNA的表达伴随着成熟B细胞增强子的完全激活和完全去甲基化。对应于iHMR转录起始位点的保守序列特征，包括可辨别的TATA基序，表明这些区域中转录的保守功能作用。类似地，我们探索了灵长类动物特异性和人类群体在iHMR上的变异，发现虽然增强子iHMR在序列和甲基化状态方面比任何其他功能类别都更加可变，但TATA盒的保守性高度预测了iHMR的维持，反映了序列可塑性和转录信号对iHMR建立的影响。总的来说，我们的分析使我们能够构建一个三步时间轴，其中（1）基因间DHS在干细胞中预先建立，（2）血液特异性基因间DHS的部分去甲基化发生在血液祖细胞中，（3）完整的iHMR形成和转录与淋巴特异性细胞中的增强子激活一致。
Deep sequencing of mammalian DNA methylomes has uncovered a previously unpredicted number of discrete hypomethylated regions in intergenic space (iHMRs). Here, we combined whole-genome bisulfite sequencing data with extensive gene expression and chromatin-state data to define functional classes of iHMRs, and to reconstruct the dynamics of their establishment in a developmental setting. Comparing HMR profiles in embryonic stem and primary blood cells, we show that iHMRs mark an exclusive subset of active DNase hypersensitive sites (DHS), and that both developmentally constitutive and cell-type-specific iHMRs display chromatin states typical of distinct regulatory elements. We also observe that iHMR changes are more predictive of nearby gene activity than the promoter HMR itself, and that expression of noncoding RNAs within the iHMR accompanies full activation and complete demethylation of mature B cell enhancers. Conserved sequence features corresponding to iHMR transcript start sites, including a discernible TATA motif, suggest a conserved, functional role for transcription in these regions. Similarly, we explored both primate-specific and human population variation at iHMRs, finding that while enhancer iHMRs are more variable in sequence and methylation status than any other functional class, conservation of the TATA box is highly predictive of iHMR maintenance, reflecting the impact of sequence plasticity and transcriptional signals on iHMR establishment. Overall, our analysis allowed us to construct a three-step timeline in which (1) intergenic DHS are pre-established in the stem cell, (2) partial demethylation of blood-specific intergenic DHSs occurs in blood progenitors, and (3) complete iHMR formation and transcription coincide with enhancer activation in lymphoid-specified cells.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
9.8
作者：
ENCODE Project Consortium
通讯作者：
ENCODE Project Consortium
影响因子：
14.9
作者：
Sérandour AA;Avner S;Oger F;Bizot M;Percevault F;Lucchetti-Miganeh C;Palierne G;Gheeraert C;Barloy-Hubler F;Péron CL;Madigou T;Durand E;Froguel P;Staels B;Lefebvre P;Métivier R;Eeckhoute J;Salbert G
通讯作者：
Salbert G
R环的形成是未甲基化的人类CpG岛启动子的独特特征。
影响因子：
16
作者：
Ginno PA;Lott PL;Christensen HC;Korf I;Chédin F
通讯作者：
Chédin F
影响因子：
4
作者：
Arnosti, DN;Kulkarni, MM
通讯作者：
Kulkarni, MM