Co-regulation of paralog genes in the three-dimensional chromatin architecture.
Co-regulation of paralog genes in the three-dimensional chromatin architecture.
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DOI：
10.1093/nar/gkw813
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发表时间：
2017-01-09
影响因子：
14.9
通讯作者：
Andrade-Navarro MA
中科院分区：
文献类型：
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作者：
Ibn-Salem J;Muro EM;Andrade-Navarro MA
副同源基因产生于进化过程中的基因复制事件，这通常会导致相似的蛋白质在共同的途径和蛋白质复合物中合作。因此，类似物显示了基因表达的相关性，而共同调节的机制尚不清楚。在真核生物中，基因通过与基因启动子的环相互作用在一定程度上受到远端增强子元件的调控。这些环相互作用可以通过全基因组染色质构象捕获（Hi-C）实验来测量，该实验揭示了称为拓扑相关结构域（tad）的自相互作用区域。我们假设平行细胞共享共同的调节机制，从而根据tad协调表达。为了验证这一假设，我们将不同组织中的人类基因表达数据、全基因组增强子-启动子关联以及人类、小鼠和狗基因组中的Hi-C实验相结合。我们发现，在相同的TAD中，同源基因对的共定位丰富，共享比预期更多的共同增强子元件，并且在大基因组距离上增加了接触频率。综上所述，我们的研究结果表明，类似物不仅在线性基因组中具有共同的调控机制，而且在三维染色质结构中也有聚集。这使得在不同细胞类型上的相似物的协调表达成为可能，并表明功能基因组组织中的进化限制。
Paralog genes arise from gene duplication events during evolution, which often lead to similar proteins that cooperate in common pathways and in protein complexes. Consequently, paralogs show correlation in gene expression whereby the mechanisms of co-regulation remain unclear. In eukaryotes, genes are regulated in part by distal enhancer elements through looping interactions with gene promoters. These looping interactions can be measured by genome-wide chromatin conformation capture (Hi-C) experiments, which revealed self-interacting regions called topologically associating domains (TADs). We hypothesize that paralogs share common regulatory mechanisms to enable coordinated expression according to TADs. To test this hypothesis, we integrated paralogy annotations with human gene expression data in diverse tissues, genome-wide enhancer–promoter associations and Hi-C experiments in human, mouse and dog genomes. We show that paralog gene pairs are enriched for co-localization in the same TAD, share more often common enhancer elements than expected and have increased contact frequencies over large genomic distances. Combined, our results indicate that paralogs share common regulatory mechanisms and cluster not only in the linear genome but also in the three-dimensional chromatin architecture. This enables concerted expression of paralogs over diverse cell-types and indicate evolutionary constraints in functional genome organization.