GC skew at the 5' and 3' ends of human genes links R-loop formation to epigenetic regulation and transcription termination.
GC skew at the 5' and 3' ends of human genes links R-loop formation to epigenetic regulation and transcription termination.
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DOI：
10.1101/gr.158436.113
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发表时间：
2013-10
期刊：
影响因子：
7
通讯作者：
Chédin F
中科院分区：
文献类型：
--
作者：
Ginno PA;Lim YW;Lott PL;Korf I;Chédin F
鸟嘌呤和胞嘧啶分布中的链不对称性（通过GC偏斜测量）使DNA序列在转录时倾向于R环形成。先前的工作揭示了GC偏斜和R环形成与人类基因组中的一组核心未甲基化CpG岛（CGI）启动子相关。在这里，我们表明，GC偏斜可以区分四类启动子，包括三种类型的CGI启动子，每一个与独特的表观遗传和基因本体签名。特别是，我们确定了一个强大的CGI启动子和一个弱的类，并表明这些基因座是丰富的不同的染色体领域反映了其保护对DNA甲基化的内在力量。有趣的是，我们发现强CGI启动子从X染色体中耗尽，而弱CGI富集，这与剂量补偿期间DNA甲基化的获得一致。此外，我们确定了第三类CGI启动子的基础上，其独特的GC偏斜配置文件，并表明，这个基因集是丰富的Polycomb组的目标。最后，我们发现近2000个基因在其3′端具有GC偏斜，并且这些基因优先位于基因密集区域并且倾向于紧密排列。因此，R环的基因组分析表明，大部分末端GC偏斜的基因在其3′端形成R环，这与这些结构在允许有效转录终止中的作用一致。总而言之，我们表明，GC偏斜和R环的形成提供了显着的见解表观遗传调控，基因组组织和人类基因的功能。
Strand asymmetry in the distribution of guanines and cytosines, measured by GC skew, predisposes DNA sequences toward R-loop formation upon transcription. Previous work revealed that GC skew and R-loop formation associate with a core set of unmethylated CpG island (CGI) promoters in the human genome. Here, we show that GC skew can distinguish four classes of promoters, including three types of CGI promoters, each associated with unique epigenetic and gene ontology signatures. In particular, we identify a strong and a weak class of CGI promoters and show that these loci are enriched in distinct chromosomal territories reflecting the intrinsic strength of their protection against DNA methylation. Interestingly, we show that strong CGI promoters are depleted from the X chromosome while weak CGIs are enriched, a property consistent with the acquisition of DNA methylation during dosage compensation. Furthermore, we identify a third class of CGI promoters based on its unique GC skew profile and show that this gene set is enriched for Polycomb group targets. Lastly, we show that nearly 2000 genes harbor GC skew at their 3′ ends and that these genes are preferentially located in gene-dense regions and tend to be closely arranged. Genomic profiling of R-loops accordingly showed that a large proportion of genes with terminal GC skew form R-loops at their 3′ ends, consistent with a role for these structures in permitting efficient transcription termination. Altogether, we show that GC skew and R-loop formation offer significant insights into the epigenetic regulation, genomic organization, and function of human genes.
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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：
7.7
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通讯作者：
Klose RJ
影响因子：
7
作者：
Cayrou, Christelle;Coulombe, Philippe;Mechali, Marcel
通讯作者：
Mechali, Marcel
影响因子：
14.9
作者：
DUNN, K;GRIFFITH, JD
通讯作者：
GRIFFITH, JD
影响因子：
4.4
作者：
Feltus, F. Alex;Lee, Eva K.;Vertino, Paula M.
通讯作者：
Vertino, Paula M.