Brain cell type–specific enhancer–promoter interactome maps and disease-risk association

Alexi Nott; Inge R. Holtman; Nicole G. Coufal; Johannes C. M. Schlachetzki; Miao Yu; Rong Hu; Claudia Z. Han; Monique Pena; Jiayang Xiao; Yin Wu; Zahara Keulen; Martina P. Pasillas; Carolyn O’Connor; Christian K. Nickl; Simon T. Schafer; Zeyang Shen; Robert A. Rissman; James B. Brewer; David Gosselin; David D. Gonda; Michael L. Levy; Michael G. Rosenfeld; Graham McVicker; Fred H. Gage; Bing Ren; Christopher K. Glass

doi:10.1126/science.aay0793

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Brain cell type–specific enhancer–promoter interactome maps and disease-risk association

Alexi Nott ¹,*,
Inge R. Holtman ¹,²,*,
Nicole G. Coufal ³,⁴,*,
Johannes C. M. Schlachetzki¹,
Miao Yu⁵,
Rong Hu⁵,
Claudia Z. Han ¹,
Monique Pena³,
Jiayang Xiao³,
Yin Wu³,
Zahara Keulen³,
Martina P. Pasillas¹,
Carolyn O’Connor ⁶,
Christian K. Nickl¹,
Simon T. Schafer³,
Zeyang Shen¹,⁷,
Robert A. Rissman⁸,⁹,
James B. Brewer ⁸,
David Gosselin¹,¹⁰,
David D. Gonda¹¹,
Michael L. Levy¹¹,
Michael G. Rosenfeld ¹²,
Graham McVicker¹³,
Fred H. Gage ³,
Bing Ren⁵,¹⁴,
Christopher K. Glass ¹,¹⁵,†

¹Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
²Section Molecular Neurobiology, Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands.
³Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁴Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
⁵Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
⁶Flow Cytometry Core Facility, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁷Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁸Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁹Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
¹⁰Centre de Recherche du Centre Hospitalier Universitaire de Québec–Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada.
¹¹Department of Neurosurgery, University of California, San Diego–Rady Children’s Hospital, San Diego, CA 92123, USA.
¹²Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹³The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
¹⁴Department of Cellular and Molecular Medicine, Center for Epigenomics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
¹⁵Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

↵†Corresponding author. Email: ckg{at}ucsd.edu

↵* These authors contributed equally to this work.

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Science 29 Nov 2019:
Vol. 366, Issue 6469, pp. 1134-1139
DOI: 10.1126/science.aay0793

Alexi Nott

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

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Inge R. Holtman

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.Section Molecular Neurobiology, Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands.

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Nicole G. Coufal

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.

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Johannes C. M. Schlachetzki

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

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Miao Yu

Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.

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Rong Hu

Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.

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Claudia Z. Han

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

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Monique Pena

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Jiayang Xiao

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Yin Wu

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Zahara Keulen

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Martina P. Pasillas

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

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Carolyn O’Connor

Flow Cytometry Core Facility, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Christian K. Nickl

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

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Simon T. Schafer

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Zeyang Shen

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.

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Robert A. Rissman

Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.

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James B. Brewer

Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.

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David Gosselin

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.Centre de Recherche du Centre Hospitalier Universitaire de Québec–Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada.

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David D. Gonda

Department of Neurosurgery, University of California, San Diego–Rady Children’s Hospital, San Diego, CA 92123, USA.

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Michael L. Levy

Department of Neurosurgery, University of California, San Diego–Rady Children’s Hospital, San Diego, CA 92123, USA.

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Michael G. Rosenfeld

Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

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Graham McVicker

The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Fred H. Gage

Section Molecular Neurobiology, Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands.

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Bing Ren

Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Christopher K. Glass

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.Department of Cellular and Molecular Medicine, Center for Epigenomics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.

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For correspondence: ckg@ucsd.edu

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Linking enhancers to disease

Enhancers are genomic regions that regulate gene expression, sometimes in a cell-dependent manner. However, most of our knowledge of human brain cell–type enhancers derives from studies of bulk human brain tissue. Nott et al. examined chromatin and promoter activity in cell nuclei isolated from human brains. Genetic variants associated with brain traits and disease showed cell-specific patterns of enhancer enrichment. These data indicate that Alzheimer's disease is regulated by genetic variants within microglial cells, whereas psychiatric diseases tend to affect neurons.

Science, this issue p. 1134

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Brain cell type–specific enhancer–promoter interactome maps and disease-risk association

Linking enhancers to disease

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