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Discovery of an autoimmunity-associated IL2RA enhancer by unbiased targeting of transcriptional activation

Dimitre R. Simeonov, Benjamin G. Gowen, Mandy Boontanrart, Theodore Roth, Youjin Lee, Alice Chan, Michelle L. Nguyen, Rachel E. Gate, Meena Subramaniam, Jonathan M. Woo, Therese Mitros, Graham J. Ray, Nicolas L. Bray, Gemma L. Curie, Nicki Naddaf, Eric Boyer, Frederic Van Gool, Kathrin Schumann, Mark J. Daly, Kyle K. Fahr, Chun Ye, Jeffrey A. Bluestone, Mark S. Anderson, Jacob E. Corn, Alexander Marson
doi: https://doi.org/10.1101/091843
Dimitre R. Simeonov
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
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Benjamin G. Gowen
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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Mandy Boontanrart
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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Theodore Roth
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
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Youjin Lee
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
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Alice Chan
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
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Michelle L. Nguyen
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
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Rachel E. Gate
6Department of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics (IHG), University of California, San Francisco, CA 94143, USA.
7Biological and Medical Informatics Graduate Program, University of California, San Francisco, CA, 94158, USA.
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Meena Subramaniam
6Department of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics (IHG), University of California, San Francisco, CA 94143, USA.
7Biological and Medical Informatics Graduate Program, University of California, San Francisco, CA, 94158, USA.
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Jonathan M. Woo
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
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Therese Mitros
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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Graham J. Ray
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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Nicolas L. Bray
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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Gemma L. Curie
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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Nicki Naddaf
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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Eric Boyer
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
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Frederic Van Gool
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
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Kathrin Schumann
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
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Mark J. Daly
8Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
9Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
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Kyle K. Fahr
10Illumina Inc., 5200 Illumina Way, San Diego, CA, 92122, USA,
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Chun Ye
6Department of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics (IHG), University of California, San Francisco, CA 94143, USA.
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Jeffrey A. Bluestone
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
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Mark S. Anderson
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
11Department of Medicine, University of California, San Francisco, CA 94143, USA.
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Jacob E. Corn
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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Alexander Marson
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
3Diabetes Center, University of California, San Francisco, CA 94143, USA.
4Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA
11Department of Medicine, University of California, San Francisco, CA 94143, USA.
12UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA.
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  • For correspondence: alexander.marson@ucsf.edu jcorn@berkeley.edu
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Abstract

The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell type-specific transcriptional programs and responses to specific extracellular cues 1-3. In order to understand the mechanisms by which non-coding genetic variation contributes to disease, systematic mapping of functional enhancers and their biological contexts is required. Here, we develop an unbiased discovery platform that can identify enhancers for a target gene without prior knowledge of their native functional context. We used tiled CRISPR activation (CRISPRa) to synthetically recruit transcription factors to sites across large genomic regions (>100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA (interleukin-2 receptor alpha; CD25). We identified several CRISPRa responsive elements (CaREs) with stimulation-dependent enhancer activity, including an IL2RA enhancer that harbors an autoimmunity risk variant. Using engineered mouse models and genome editing of human primary T cells, we found that sequence perturbation of the disease-associated IL2RA enhancer does not block IL2RA expression, but rather delays the timing of gene activation in response to specific extracellular signals. This work develops an approach to rapidly identify functional enhancers within non-coding regions, decodes a key human autoimmunity association, and suggests a general mechanism by which genetic variation can cause immune dysfunction.

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Posted December 05, 2016.
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Discovery of an autoimmunity-associated IL2RA enhancer by unbiased targeting of transcriptional activation
Dimitre R. Simeonov, Benjamin G. Gowen, Mandy Boontanrart, Theodore Roth, Youjin Lee, Alice Chan, Michelle L. Nguyen, Rachel E. Gate, Meena Subramaniam, Jonathan M. Woo, Therese Mitros, Graham J. Ray, Nicolas L. Bray, Gemma L. Curie, Nicki Naddaf, Eric Boyer, Frederic Van Gool, Kathrin Schumann, Mark J. Daly, Kyle K. Fahr, Chun Ye, Jeffrey A. Bluestone, Mark S. Anderson, Jacob E. Corn, Alexander Marson
bioRxiv 091843; doi: https://doi.org/10.1101/091843
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Discovery of an autoimmunity-associated IL2RA enhancer by unbiased targeting of transcriptional activation
Dimitre R. Simeonov, Benjamin G. Gowen, Mandy Boontanrart, Theodore Roth, Youjin Lee, Alice Chan, Michelle L. Nguyen, Rachel E. Gate, Meena Subramaniam, Jonathan M. Woo, Therese Mitros, Graham J. Ray, Nicolas L. Bray, Gemma L. Curie, Nicki Naddaf, Eric Boyer, Frederic Van Gool, Kathrin Schumann, Mark J. Daly, Kyle K. Fahr, Chun Ye, Jeffrey A. Bluestone, Mark S. Anderson, Jacob E. Corn, Alexander Marson
bioRxiv 091843; doi: https://doi.org/10.1101/091843

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