Inactive or moderately active human promoters are enriched for inter-individual epialleles.
Inactive or moderately active human promoters are enriched for inter-individual epialleles.
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DOI：
10.1186/gb-2013-14-5-r43
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发表时间：
2013-05-25
期刊：
影响因子：
12.3
通讯作者：
Rakyan VK
中科院分区：
文献类型：
--
作者：
Gemma C;Ramagopalan SV;Down TA;Beyan H;Hawa MI;Holland ML;Hurd PJ;Giovannoni G;Leslie RD;Ebers GC;Rakyan VK
在许多真核物种中观察到由于遗传、环境或随机影响而导致的个体间表观遗传变异。然而，在哺乳动物中，表等位基因变异的分子性质尚不清楚，部分原因是对 DNA 甲基化的关注有限。在这里，我们报告了哺乳动物表观等位基因的首次基因组规模研究，整合了基因组、甲基组学、转录组学和组蛋白状态信息。首先，在一个小样本集中，我们证明非基因决定的个体间差异甲基化区域（iiDMR）可以在至少 2 年内保持暂时稳定。然后，我们通过组蛋白变体 H2A.Z 水平的个体间差异来测量，表明 iiDMR 与染色质状态的变化相关。然而，启动子iiDMR与基因表达的相关性可以忽略不计，并且没有通过整合H2A.Z信息而得到改善。我们发现，大多数启动子表观等位基因，无论是遗传决定的还是非遗传决定的，都与低水平的转录活性相关，在人类胚胎干细胞中，管家基因被耗尽，H3K4me3 被耗尽/H3K27me3 被富集，或者缺乏这两种标记。 iiDMR 在相对转录不活跃区域的优先富集在更大的独立队列中得到了验证，并且让人想起之前对在各种癌症、体外细胞培养和衰老中经历高甲基化的启动子进行的观察。我们的工作确定了人类表观等位基因变异的潜在关键特征，包括非遗传决定的表观等位基因的时间稳定性以及伴随的染色质状态扰动。此外，我们的工作表明在正常变异、癌症和衰老的背景下观察到的个体间表观等位基因之间存在一种新的机制联系。
Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. In mammals, however, the molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. Here we report the first genome-scale investigation of mammalian epialleles that integrates genomic, methylomic, transcriptomic and histone state information. First, in a small sample set, we demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable over at least 2 years. Then, we show that iiDMRs are associated with changes in chromatin state as measured by inter-individual differences in histone variant H2A.Z levels. However, the correlation of promoter iiDMRs with gene expression is negligible and not improved by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for housekeeping genes, and either depleted for H3K4me3/enriched for H3K27me3 or lacking both these marks in human embryonic stem cells. The preferential enrichment of iiDMRs at regions of relative transcriptional inactivity validates in a larger independent cohort, and is reminiscent of observations previously made for promoters that undergo hypermethylation in various cancers, in vitro cell culture and ageing. Our work identifies potential key features of epiallelic variation in humans, including temporal stability of non-genetically determined epialleles, and concomitant perturbations of chromatin state. Furthermore, our work suggests a novel mechanistic link among inter-individual epialleles observed in the context of normal variation, cancer and ageing.
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DOI：
10.1126/science.1212959
发表时间：
2011-10-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Schmitz RJ;Schultz MD;Lewsey MG;O'Malley RC;Urich MA;Libiger O;Schork NJ;Ecker JR
通讯作者：
Ecker JR
影响因子：
3.7
作者：
Sandoval, Juan;Heyn, Holger A.;Esteller, Manel
通讯作者：
Esteller, Manel
影响因子：
7
作者：
Cuddapah, Suresh;Jothi, Raja;Zhao, Keji
通讯作者：
Zhao, Keji
DOI：
10.1038/nrg3000
发表时间：
2011-07-12
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.5
作者：
Gertz J;Varley KE;Reddy TE;Bowling KM;Pauli F;Parker SL;Kucera KS;Willard HF;Myers RM
通讯作者：
Myers RM