Coding exons function as tissue-specific enhancers of nearby genes.
Coding exons function as tissue-specific enhancers of nearby genes.
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DOI：
10.1101/gr.133546.111
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发表时间：
2012-06
期刊：
影响因子：
7
通讯作者：
Ahituv N
中科院分区：
文献类型：
--
作者：
Birnbaum RY;Clowney EJ;Agamy O;Kim MJ;Zhao J;Yamanaka T;Pappalardo Z;Clarke SL;Wenger AM;Nguyen L;Gurrieri F;Everman DB;Schwartz CE;Birk OS;Bejerano G;Lomvardas S;Ahituv N
增强子是必不可少的基因调控元件，其改变可导致物种之间的形态差异、发育异常和人类疾病。目前鉴定增强子的策略主要集中在非编码序列上，并倾向于排除蛋白质编码序列。在这里，我们分析了25个可用的ChIP-seq数据集，这些数据集以无偏的方式识别增强子（H3K4me1， H3K27ac和EP300），以确定重叠外显子的峰。我们发现，平均7%的ChIP-seq峰与编码外显子重叠（排除与第一外显子重叠的峰后）。通过小鼠和斑马鱼的增强子实验，我们证明了这些外显子增强子（eExons）候选子可以作为其邻近基因的增强子，并且外显子序列是增强子活性所必需的。通过ChIP、3C和DNA FISH，我们进一步发现其中一个外显子肢体增强子Dync1i1外显子15具有活跃的增强子标记，并与900 kb外的Dlx5/6启动子区域发生物理相互作用。此外，在人类染色体异常中去除它可能导致与DLX5/6相关的分裂手足畸形1 （SHFM1）。这些结果表明，DNA序列可以具有双重功能，在一个组织中作为编码外显子，在另一个组织中作为附近基因的增强子，这表明编码突变引起的表型不仅可以由蛋白质改变引起，还可以通过破坏另一个基因的调节引起。
Enhancers are essential gene regulatory elements whose alteration can lead to morphological differences between species, developmental abnormalities, and human disease. Current strategies to identify enhancers focus primarily on noncoding sequences and tend to exclude protein coding sequences. Here, we analyzed 25 available ChIP-seq data sets that identify enhancers in an unbiased manner (H3K4me1, H3K27ac, and EP300) for peaks that overlap exons. We find that, on average, 7% of all ChIP-seq peaks overlap coding exons (after excluding for peaks that overlap with first exons). By using mouse and zebrafish enhancer assays, we demonstrate that several of these exonic enhancer (eExons) candidates can function as enhancers of their neighboring genes and that the exonic sequence is necessary for enhancer activity. Using ChIP, 3C, and DNA FISH, we further show that one of these exonic limb enhancers, Dync1i1 exon 15, has active enhancer marks and physically interacts with Dlx5/6 promoter regions 900 kb away. In addition, its removal by chromosomal abnormalities in humans could cause split hand and foot malformation 1 (SHFM1), a disorder associated with DLX5/6. These results demonstrate that DNA sequences can have a dual function, operating as coding exons in one tissue and enhancers of nearby gene(s) in another tissue, suggesting that phenotypes resulting from coding mutations could be caused not only by protein alteration but also by disrupting the regulation of another gene.
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影响因子：
14.9
作者：
Dong X;Navratilova P;Fredman D;Drivenes Ø;Becker TS;Lenhard B
通讯作者：
Lenhard B
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：
14.8
作者：
Iovine, M. Katryn
通讯作者：
Iovine, M. Katryn
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
DOI：
10.1038/nrm2804
发表时间：
2009-12
期刊：
Nature reviews. Molecular cell biology
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