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

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TitleLearning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism.
Publication TypeJournal Article
Year of Publication2018
AuthorsKoberstein, JN, Poplawski, SG, Wimmer, ME, Porcari, G, Kao, C, Gomes, B, Risso, D, Hakonarson, H, Zhang, NR, Schultz, RT, Abel, T, Peixoto, L
JournalSci Signal
Date Published2018 01 16
KeywordsAdolescent, Alternative Splicing, Animals, Autistic Disorder, Case-Control Studies, Child, Child, Preschool, Chromatin Assembly and Disassembly, Cohort Studies, Epigenesis, Genetic, Female, Gene Expression Regulation, Hippocampus, Humans, Learning, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Regulatory Sequences, Nucleic Acid, RNA, Untranslated

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.

Alternate JournalSci Signal
PubMed ID29339533
PubMed Central IDPMC6180319
Grant ListT32 HL007953 / HL / NHLBI NIH HHS / United States
T32 NS007413 / NS / NINDS NIH HHS / United States
R01 MH087463 / MH / NIMH NIH HHS / United States
RC1 MH088791 / MH / NIMH NIH HHS / United States
U54 HD086984 / HD / NICHD NIH HHS / United States