5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells.
5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells.
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DOI：
10.1371/journal.pgen.1006966
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发表时间：
2017-09
期刊：
影响因子：
4.5
通讯作者：
Fessing MY
中科院分区：
文献类型：
--
作者：
Poterlowicz K;Yarker JL;Malashchuk I;Lajoie BR;Mardaryev AN;Gdula MR;Sharov AA;Kohwi-Shigematsu T;Botchkarev VA;Fessing MY
哺乳动物基因组含有几十个大的（>0.5 Mbp）谱系特异性基因位点，这些基因位点含有功能相关的基因。然而，空间染色质折叠，增强子-启动子网络的组织及其与这些基因座中拓扑相关结构域（TADs）的相关性仍然知之甚少。TADs是基因组折叠的主要单位，代表DNA区域，在该区域内，DNA在跨DNA边界上的相互作用更频繁和更不频繁。在这里，我们使用染色质构象捕获碳拷贝（5C）技术来表征空间染色质相互作用网络在3.1 Mb表皮分化复合物（EDC）基因座窝藏61个功能相关的基因，显示在表皮中的终末角质形成细胞分化过程中的谱系特异性激活。通过3D-FISH验证的5C数据表明，EDC基因座被组织成几个TAD，基于它们的转录活性和基因富集或基因贫乏状态，显示出不同的谱系特异性染色质相互作用网络。5C结果与增强子特异性组蛋白修饰（H3 K4 me 1和H3 K27 ac）的全基因组研究的相关性表明，涉及角质形成细胞EDC基因座处富含基因的TADs的大多数空间染色质相互作用包括连接基因启动子和增强子的胞内和胞间相互作用网络。与胸腺细胞相比，其中EDC位点大多是转录失活的，这些相互作用被发现是角质形成细胞特异性的。在角质形成细胞中，启动子-增强子锚定区中的基因丰富的转录活性的TADs富集的染色质结构蛋白CTCF，Rad 21和染色质重塑Brg 1的结合。与富含基因的TADs相反，缺乏基因的TADs显示彼此之间的优先空间接触，不含活性增强子，并且显示角质形成细胞中CTCF、Rad 21和Brg 1的结合减少。因此，在皮肤上皮细胞中的多个EDC基因座处的基因启动子和增强子之间的空间相互作用是细胞类型特异性的，并且涉及TADs内以及不同基因丰富的TADs之间的广泛接触，形成谱系特异性转录的框架。不同细胞类型中的基因活性程序控制多细胞生物体的发育和稳态。空间基因组组织通过促进或限制基因启动子和远程基因增强子之间的接触来控制基因活性。功能相关的共调节基因通常位于基因组位点中。非常大的共调节基因位点的空间组织仍然知之甚少。我们分析了表皮分化复合物（EDC）基因座中的空间接触网络，该基因座包含61个在表皮细胞和胸腺细胞的表皮分化过程中激活的共调节基因，其中该基因座大多是无活性的。我们的分析表明，EDC中的基因丰富和基因贫乏区域被组织在单独的拓扑关联结构域（TADs）中。我们进一步发现EDC基因座中的空间接触主要是细胞类型特异性的。在角质形成细胞中，这种接触将基因启动子与基因增强子连接在富含基因的TAD内和之间。染色质结构蛋白CTCF和Rad 21与染色质重塑剂Brg 1一起经常在角质形成细胞中的空间接触基因启动子和增强子附近结合。与富含基因的TAD相比，缺乏基因的TAD显示出彼此之间的优先空间接触，不含活性增强子，并且显示出CTCF、Rad 21和Brg 1的结合减少。这些数据说明了谱系特异性转录所需的染色质网络是如何在皮肤上皮细胞中组织起来的，并证明了EDC基因座上涉及基因启动子和增强子的空间相互作用不受限制，并且与内-内相互作用一起涉及不同TADs之间的广泛接触。
Mammalian genomes contain several dozens of large (>0.5 Mbp) lineage-specific gene loci harbouring functionally related genes. However, spatial chromatin folding, organization of the enhancer-promoter networks and their relevance to Topologically Associating Domains (TADs) in these loci remain poorly understood. TADs are principle units of the genome folding and represents the DNA regions within which DNA interacts more frequently and less frequently across the TAD boundary. Here, we used Chromatin Conformation Capture Carbon Copy (5C) technology to characterize spatial chromatin interaction network in the 3.1 Mb Epidermal Differentiation Complex (EDC) locus harbouring 61 functionally related genes that show lineage-specific activation during terminal keratinocyte differentiation in the epidermis. 5C data validated by 3D-FISH demonstrate that the EDC locus is organized into several TADs showing distinct lineage-specific chromatin interaction networks based on their transcription activity and the gene-rich or gene-poor status. Correlation of the 5C results with genome-wide studies for enhancer-specific histone modifications (H3K4me1 and H3K27ac) revealed that the majority of spatial chromatin interactions that involves the gene-rich TADs at the EDC locus in keratinocytes include both intra- and inter-TAD interaction networks, connecting gene promoters and enhancers. Compared to thymocytes in which the EDC locus is mostly transcriptionally inactive, these interactions were found to be keratinocyte-specific. In keratinocytes, the promoter-enhancer anchoring regions in the gene-rich transcriptionally active TADs are enriched for the binding of chromatin architectural proteins CTCF, Rad21 and chromatin remodeler Brg1. In contrast to gene-rich TADs, gene-poor TADs show preferential spatial contacts with each other, do not contain active enhancers and show decreased binding of CTCF, Rad21 and Brg1 in keratinocytes. Thus, spatial interactions between gene promoters and enhancers at the multi-TAD EDC locus in skin epithelial cells are cell type-specific and involve extensive contacts within TADs as well as between different gene-rich TADs, forming the framework for lineage-specific transcription. Gene activity programmes in different cell types control development and homeostasis of multi-cellular organisms. Spatial genome organization controls gene activity by facilitating or restricting contacts between gene promoters and remote gene enhancers. Functionally related co-regulated genes are often located together in genomes loci. The spatial organization of very large co-regulated gene loci remains poorly understood. We analyse the spatial contact network in the Epidermal Differentiation Complex (EDC) locus that contains 61 co-regulated genes activated during epidermal differentiation in epidermal cells and thymocytes, where the locus is mostly inactive. Our analysis demonstrated that the gene-rich and gene-poor regions in the EDC are organized in separate Topologically Associating Domains (TADs). We further found that spatial contact in the EDC locus is mostly cell type specific. In keratinocytes such contacts connect gene promoters with gene enhancers both within and between gene-rich TADs. Chromatin architectural proteins CTCF and Rad21 together with chromatin remodeller Brg1 were often bound near the spatially contacting gene promoters and enhancers in keratinocytes. In contrast to gene-rich TADs, gene-poor TADs show preferential spatial contacts with each other, do not contain active enhancers and show decreased binding of CTCF, Rad21 and Brg1. These data illustrate how the chromatin networks required for lineage-specific transcription are organized in skin epithelial cells and demonstrate that spatial interactions involving gene promoters and enhancers at the EDC locus are not restricted by the TAD boundaries and involve, together with intra-TAD interactions, the extensive contacts between the different TADs.
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