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

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Sci. Signal.  16 Jan 2018:
Vol. 11, Issue 513, eaan6500
DOI: 10.1126/scisignal.aan6500

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Deciphering the chromatin in learning and autism

Both development and learning are shaped through epigenetics—modifications to the DNA or chromatin that alter gene expression without changing the underlying DNA sequence. The intellectual disorder ASD (autism spectrum disorder) is idiopathic, but it is associated with changes in gene expression that alter the development of neuronal circuitry in the brain and impair some forms of learning. Using a new technique called DEScan, Koberstein et al. explored learning-induced changes to the epigenetic landscape of the hippocampus (a region critical for memory) in mice. They found that learning was mediated through changes to regulatory regions, particularly the activation of alternative promoters, of many genes associated with ASD. These findings identify an epigenetic source of one gene alteration associated with ASD and, more broadly, demonstrate a new technique for exploring learning disorders in animal models.

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 (SHANK3 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.

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