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Enhancer connectome in primary human cells reveals target genes of disease-associated DNA elements

Maxwell R. Mumbach, Ansuman T. Satpathy, Evan A. Boyle, Chao Dai, Benjamin G. Gowen, Seung Woo Cho, Michelle L. Nguyen, Adam J. Rubin, Jeffrey M. Granja, Katelynn R. Kazane, Yuning Wei, Trieu Nguyen, Peyton G. Greenside, M. Ryan Corces, Josh Tycko, Dimitre R. Simeonov, Nabeela Suliman, Rui Li, Jin Xu, Ryan A. Flynn, Anshul Kundaje, Paul A. Khavari, Alexander Marson, Jacob E. Corn, Thomas Quertermous, William J. Greenleaf, Howard Y. Chang
doi: https://doi.org/10.1101/178269
Maxwell R. Mumbach
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Ansuman T. Satpathy
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Evan A. Boyle
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Chao Dai
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Benjamin G. Gowen
4Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
5Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA
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Seung Woo Cho
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Michelle L. Nguyen
6Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
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Adam J. Rubin
7Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
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Jeffrey M. Granja
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Katelynn R. Kazane
4Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
5Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA
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Yuning Wei
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Trieu Nguyen
8Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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Peyton G. Greenside
2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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M. Ryan Corces
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Josh Tycko
2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Dimitre R. Simeonov
6Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
10Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
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Nabeela Suliman
2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Rui Li
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Jin Xu
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Ryan A. Flynn
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Anshul Kundaje
2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Paul A. Khavari
7Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
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Alexander Marson
5Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA
6Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
8Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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Jacob E. Corn
4Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
5Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA
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Thomas Quertermous
9Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
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William J. Greenleaf
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
8Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
11Department of Applied Physics, Stanford University, Stanford, CA, 94305, USA
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Howard Y. Chang
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
7Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
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ABSTRACT

The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here, we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naïve T cells to T helper 17 cells or regulatory T cells creates subtype-specific enhancer-promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a four-fold increase of potential target genes for autoimmune and cardiovascular diseases.

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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-ND 4.0 International license.
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Posted August 30, 2017.
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Enhancer connectome in primary human cells reveals target genes of disease-associated DNA elements
Maxwell R. Mumbach, Ansuman T. Satpathy, Evan A. Boyle, Chao Dai, Benjamin G. Gowen, Seung Woo Cho, Michelle L. Nguyen, Adam J. Rubin, Jeffrey M. Granja, Katelynn R. Kazane, Yuning Wei, Trieu Nguyen, Peyton G. Greenside, M. Ryan Corces, Josh Tycko, Dimitre R. Simeonov, Nabeela Suliman, Rui Li, Jin Xu, Ryan A. Flynn, Anshul Kundaje, Paul A. Khavari, Alexander Marson, Jacob E. Corn, Thomas Quertermous, William J. Greenleaf, Howard Y. Chang
bioRxiv 178269; doi: https://doi.org/10.1101/178269
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Enhancer connectome in primary human cells reveals target genes of disease-associated DNA elements
Maxwell R. Mumbach, Ansuman T. Satpathy, Evan A. Boyle, Chao Dai, Benjamin G. Gowen, Seung Woo Cho, Michelle L. Nguyen, Adam J. Rubin, Jeffrey M. Granja, Katelynn R. Kazane, Yuning Wei, Trieu Nguyen, Peyton G. Greenside, M. Ryan Corces, Josh Tycko, Dimitre R. Simeonov, Nabeela Suliman, Rui Li, Jin Xu, Ryan A. Flynn, Anshul Kundaje, Paul A. Khavari, Alexander Marson, Jacob E. Corn, Thomas Quertermous, William J. Greenleaf, Howard Y. Chang
bioRxiv 178269; doi: https://doi.org/10.1101/178269

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