Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.
Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.
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DOI：
10.1016/j.cell.2015.04.004
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发表时间：
2015-05-21
期刊：
影响因子：
64.5
通讯作者：
Mundlos S
中科院分区：
文献类型：
--
作者：
Lupiáñez DG;Kraft K;Heinrich V;Krawitz P;Brancati F;Klopocki E;Horn D;Kayserili H;Opitz JM;Laxova R;Santos-Simarro F;Gilbert-Dussardier B;Wittler L;Borschiwer M;Haas SA;Osterwalder M;Franke M;Timmermann B;Hecht J;Spielmann M;Visel A;Mundlos S
哺乳动物基因组被组织成兆级拓扑相关域（TADs）。我们证明TADs的破坏可以重新连接远程调控结构并导致致病表型。我们发现，不同的人类肢体畸形是由缺失、倒置或重复引起的，改变了tad -span位点WNT6/IHH/EPHA4/PAX3的结构。使用CRISPR/Cas基因组编辑，我们产生了具有相应重排的小鼠。在小鼠肢体组织和患者来源的成纤维细胞中，疾病相关的结构变化导致启动子和非编码DNA之间的异位相互作用，并且通常与Epha4相关的肢体增强子簇相对于TAD边界错位，并驱动位点上另一个基因的异位肢体表达。只有当变异破坏了ctcf相关的边界域时，这种重新布线才会发生。我们的研究结果证明了TADs在通过基因组结构协调基因表达方面的功能重要性，并为预测人类结构变异的致病性提供了标准，特别是在人类基因组的非编码区域。
Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.