Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

John N Koberstein; Shane G Poplawski; Mathieu E Wimmer; Giulia Porcari; Charlly Kao; Bruce Gomes; Davide Risso; Hakon Hakonarson; Nancy R Zhang; Robert T Schultz; Ted Abel; Lucia Peixoto

doi:10.1126/scisignal.aan6500

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Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

Journal article

Open access

Peer reviewed

Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

John N Koberstein, Shane G Poplawski, Mathieu E Wimmer, Giulia Porcari, Charlly Kao, Bruce Gomes, Davide Risso, Hakon Hakonarson, Nancy R Zhang, Robert T Schultz, …

Science signaling, Vol.11(513), p.eaan6500

01/16/2018

DOI: 10.1126/scisignal.aan6500

PMCID: PMC6180319

PMID: 29339533

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Abstract

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder that is associated with genetic risk factors. Most human disease-associated single-nucleotide polymorphisms (SNPs) are not located in genes but rather are in regulatory regions that control gene expression. The function of regulatory regions is determined through epigenetic mechanisms. Parallels between the cellular basis of development and the formation of long-term memory have long been recognized, particularly the role of epigenetic mechanisms in both processes. We analyzed how learning alters chromatin accessibility in the mouse hippocampus using a new high-throughput sequencing bioinformatics strategy we call DEScan (differential enrichment scan). DEScan, which enabled the analysis of data from epigenomic experiments containing multiple replicates, revealed changes in chromatin accessibility at 2365 regulatory regions-most of which were promoters. Learning-regulated promoters were active during forebrain development in mice and were enriched in epigenetic modifications indicative of bivalent promoters. These promoters were disproportionally intronic, showed a complex relationship with gene expression and alternative splicing during memory consolidation and retrieval, and were enriched in the data set relative to known ASD risk genes. Genotyping in a clinical cohort within one of these promoters ( promoter 6) revealed that the SNP rs6010065 was associated with ASD. Our data support the idea that learning recapitulates development at the epigenetic level and demonstrate that behaviorally induced epigenetic changes in mice can highlight regulatory regions relevant to brain disorders in patients.

Autistic Disorder - pathology

Alternative Splicing

Epigenesis, Genetic

Humans

Regulatory Sequences, Nucleic Acid

Child, Preschool

Male

RNA, Untranslated - genetics

Case-Control Studies

Learning

Female

Child

Autistic Disorder - genetics

Promoter Regions, Genetic

Mice, Inbred C57BL

Gene Expression Regulation

Chromatin Assembly and Disassembly

Hippocampus - pathology

Nerve Tissue Proteins - genetics

Hippocampus - metabolism

Animals

Adolescent

Mice

Polymorphism, Single Nucleotide

Cohort Studies

Details

Title: Subtitle: Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism
Creators: John N Koberstein - Department of Biomedical Sciences, Elson S. Floyd College of Medicine. Washington State University, Spokane, WA 99202, USA
Shane G Poplawski - Ibis Biosciences Inc. of Abbot, Carlsbad, CA 92008, USA
Mathieu E Wimmer - Department of Psychology and Program in Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA 19122, USA
Giulia Porcari - Vanderbilt University Medical School, Nashville, TN 37232, USA
Charlly Kao - Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY 10065, USA
Bruce Gomes - Department of Biomedical Sciences, Elson S. Floyd College of Medicine. Washington State University, Spokane, WA 99202, USA
Davide Risso - Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY 10065, USA
Hakon Hakonarson - Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Nancy R Zhang - Department of Statistics, Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA
Robert T Schultz - Center for Autism Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Ted Abel - Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Lucia Peixoto - Department of Biomedical Sciences, Elson S. Floyd College of Medicine. Washington State University, Spokane, WA 99202, USA. lucia.peixoto@wsu.edu
Resource Type: Journal article
Publication Details: Science signaling, Vol.11(513), p.eaan6500
DOI: 10.1126/scisignal.aan6500
PMID: 29339533
PMCID: PMC6180319
NLM abbreviation: Sci Signal
ISSN: 1945-0877
eISSN: 1937-9145
Publisher: United States
Grant note: K01 NS104172 / NINDS NIH HHS RC1 MH088791 / NIMH NIH HHS R01 MH087463 / NIMH NIH HHS U54 HD086984 / NICHD NIH HHS T32 HL007953 / NHLBI NIH HHS T32 NS007413 / NINDS NIH HHS
Language: English
Date published: 01/16/2018
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984025276902771

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