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

View ORCID ProfileLeina Lu, View ORCID ProfileXiaoxiao Liu, Wei-Kai Huang, View ORCID ProfilePaola 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, View ORCID ProfileYun Li, Patrick F Sullivan, Hongjun Song, Guo-li Ming, Yan Li, View ORCID ProfileFulai Jin
doi: https://doi.org/10.1101/744540
Leina Lu
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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  • ORCID record for Leina Lu
Xiaoxiao Liu
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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  • ORCID record for Xiaoxiao Liu
Wei-Kai Huang
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19035, USAGraduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Paola Giusti-Rodríguez
Department of Genetics, University of North Carolina, Chapel Hill, NC, USADepartment of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
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  • ORCID record for Paola Giusti-Rodríguez
Jian Cui
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Shanshan Zhang
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Wanying Xu
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Zhexing Wen
Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Shufeng Ma
Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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Jonathan D Rosen
Department of Biostatistics, Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA
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Zheng Xu
Department of Genetics, University of North Carolina, Chapel Hill, NC, USADepartment of Biostatistics, Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA
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Cynthia Bartels
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Riki Kawaguchi
Department of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA
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Ming Hu
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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Peter Scacheri
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Zhili Rong
Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, ChinaDermatology Hospital, Southern Medical University, Guangzhou, 510091, China
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Yun Li
Department of Genetics, University of North Carolina, Chapel Hill, NC, USADepartment of Biostatistics, Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA
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Patrick F Sullivan
Department of Genetics, University of North Carolina, Chapel Hill, NC, USADepartment of Psychiatry, University of North Carolina, Chapel Hill, NC, USAKarolinska Institute, Department of Medical Epidemiology and Biostatistics and Department of Genetics, Stockholm, Sweden
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Hongjun Song
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19035, USADepartment of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19035, USAThe Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19035, USA
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Guo-li Ming
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19035, USAGraduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19035, USADepartment of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19035, USA
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  • For correspondence: fxj45@case.edu yxl1379@case.edu gming@pennmedicine.upenn.edu
Yan Li
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USACollege of Graduate Studies, Cleveland State University, Cleveland, OH 44115, USA
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  • For correspondence: fxj45@case.edu yxl1379@case.edu gming@pennmedicine.upenn.edu
Fulai Jin
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Population and Quantitative Health Sciences, Department of Engineering & Computer Science, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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  • For correspondence: fxj45@case.edu yxl1379@case.edu gming@pennmedicine.upenn.edu
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Abstract

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 (HiCorr) 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.

Highlights

  • Low input “easy Hi-C” protocol compatible with 50-100K cells

  • Improved Hi-C bias correction allows direct observation and accurate identification of sub-TAD chromatin loops and enhancer aggregates

  • Recurrent architectural memory of somatic heterochromatin at compartment level in skin-derived hiPSCs

  • Chromatin loop, but not genome compartment, marks neural differentiation

  • Chromatin loop outperforms eQTL in defining brain GWAS target genes

Footnotes

  • ↵# Co-senior authors.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted August 22, 2019.
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Robust Hi-C chromatin loop maps in human neurogenesis and brain tissues at high-resolution
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
bioRxiv 744540; doi: https://doi.org/10.1101/744540
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Robust Hi-C chromatin loop maps in human neurogenesis and brain tissues at high-resolution
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
bioRxiv 744540; doi: https://doi.org/10.1101/744540

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