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Robust Hi-C chromatin loop maps in human neurogenesis and brain tissues at high-resolution

By Leina Lu, Xiaoxiao Liu, Wei-Kai Huang, Paola Giusti-Rodríguez, Jian Cui, Shanshan Zhang, Wanying Xu, Zhexing Wen, Shufeng Ma, Jonathan D Rosen, Zheng Xu, Cynthia Bartels, Riki Kawaguchi, Ming Hu, Peter Scacheri, Zhili Rong, Yun Li, Patrick F Sullivan, Hongjun Song, Guo-li Ming, Yan Li, Fulai Jin

Posted 22 Aug 2019
bioRxiv DOI: 10.1101/744540

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input “easy Hi-C” (eHi-C) protocol to map the 3D genome architecture in neurogenesis and brain tissues, and also developed an improved Hi-C bias-correction pipeline enabling better identification of enhancer loops or aggregates at sub-TAD level. We compared ultra-deep 3D genome maps from 10 human tissue- or cell types, with a focus on stem cells and neural development. We found several large loci in skin-derived human iPSC lines showing recurrent 3D compartmental memory of somatic heterochromatin. Chromatin loop interactions, but not genome compartments, are hallmarks of neural differentiation. Interestingly, we observed many cell type- or differentiation-specific enhancer aggregates spanning large neighborhoods, supporting a phase-separation mechanism that stabilizes enhancer contacts during development. Finally, we demonstrated that chromatin loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.

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