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Genetic determinants of chromatin accessibility and gene regulation in T cell activation across human individuals

Christine S. Cheng, Rachel E. Gate, Aviva P. Aiden, Atsede Siba, Marcin Tabaka, Dmytro Lituiev, Ido Machol, Meena Subramaniam, Muhammad Shamim, Kendrick L. Hougen, Ivo Wortman, Su-Chen Huang, Neva C. Durand, Ting Feng, Philip L. De Jager, Howard Y. Chang, Erez Lieberman Aiden, Christophe Benoist, Michael A. Beer, Chun J. Ye, Aviv Regev
doi: https://doi.org/10.1101/090241
Christine S. Cheng
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge MA 02142, USA
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Rachel E. Gate
2Institute for Human Genetics, Department of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, UCSF
3Biological and Medical Informatics Graduate Program, UCSF
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Aviva P. Aiden
4Department of Molecular and Human Genetics, the Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
5Department of Bioengineering, Rice University, Houston, TX 77030, USAs
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Atsede Siba
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge MA 02142, USA
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Marcin Tabaka
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge MA 02142, USA
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Dmytro Lituiev
2Institute for Human Genetics, Department of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, UCSF
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Ido Machol
4Department of Molecular and Human Genetics, the Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
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Meena Subramaniam
2Institute for Human Genetics, Department of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, UCSF
3Biological and Medical Informatics Graduate Program, UCSF
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Muhammad Shamim
4Department of Molecular and Human Genetics, the Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
10Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
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Kendrick L. Hougen
12Department of Biomedical Engineering, Johns Hopkins University, Baltimore, USA
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Ivo Wortman
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge MA 02142, USA
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Su-Chen Huang
4Department of Molecular and Human Genetics, the Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
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Neva C. Durand
4Department of Molecular and Human Genetics, the Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
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Ting Feng
6Division of Immunology, Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115
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Philip L. De Jager
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge MA 02142, USA
7Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
8Harvard Medical School, Boston, MA 02115, USA
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Howard Y. Chang
9Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA
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Erez Lieberman Aiden
4Department of Molecular and Human Genetics, the Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
10Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
11Department of Computer Science, Department of Computational and Applied Mathematics, Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USAs
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Christophe Benoist
6Division of Immunology, Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115
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Michael A. Beer
12Department of Biomedical Engineering, Johns Hopkins University, Baltimore, USA
13McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, USA
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Chun J. Ye
2Institute for Human Genetics, Department of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, UCSF
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  • For correspondence: aregev@broadinstitute.org jimmie.ye@ucsf.edu
Aviv Regev
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge MA 02142, USA
14Howard Hughes Medical Institute, Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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  • For correspondence: aregev@broadinstitute.org jimmie.ye@ucsf.edu
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Abstract

The vast majority of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. Here, we analyzed Assay for Transposase-Accessible Chromatin (ATAC-seq) profiles from activated primary CD4+ T cells of 105 healthy donors to identify ATAC-QTLs: genetic variants that affect chromatin accessibility. We found that ATAC-QTLs are widespread, disrupt binding sites for transcription factors known to be important for CD4+ T cell differentiation and activation, overlap and mediate expression QTLs from the same cells and are enriched for SNPs associated with autoimmune diseases. We also identified numerous pairs of ATAC-peaks with highly correlated chromatin accessibility. When we characterize 3D chromosome organization in primary CD4+ T cells by in situ-Hi-C, we found that correlated peaks tend to reside in the same chromatin contact domains, span super-enhancers, and are more impacted by ATAC-QTLs than single peaks. Thus, variability in chromatin accessibility in primary CD4+ T cells is heritable, is determined by genetic variation in a manner affected by the 3D organization of the genome, and mediates genetic effects on gene expression. Our results provide insights into how genetic variants modulate chromatin state and gene expression in primary immune cells that play a key role in many human 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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Genetic determinants of chromatin accessibility and gene regulation in T cell activation across human individuals
Christine S. Cheng, Rachel E. Gate, Aviva P. Aiden, Atsede Siba, Marcin Tabaka, Dmytro Lituiev, Ido Machol, Meena Subramaniam, Muhammad Shamim, Kendrick L. Hougen, Ivo Wortman, Su-Chen Huang, Neva C. Durand, Ting Feng, Philip L. De Jager, Howard Y. Chang, Erez Lieberman Aiden, Christophe Benoist, Michael A. Beer, Chun J. Ye, Aviv Regev
bioRxiv 090241; doi: https://doi.org/10.1101/090241
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Genetic determinants of chromatin accessibility and gene regulation in T cell activation across human individuals
Christine S. Cheng, Rachel E. Gate, Aviva P. Aiden, Atsede Siba, Marcin Tabaka, Dmytro Lituiev, Ido Machol, Meena Subramaniam, Muhammad Shamim, Kendrick L. Hougen, Ivo Wortman, Su-Chen Huang, Neva C. Durand, Ting Feng, Philip L. De Jager, Howard Y. Chang, Erez Lieberman Aiden, Christophe Benoist, Michael A. Beer, Chun J. Ye, Aviv Regev
bioRxiv 090241; doi: https://doi.org/10.1101/090241

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