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

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.

Differential chromatin accessibility in developing projection neurons is correlated with transcriptional regulation of cell fate

“…Here we have generated a resource for discovering genes and regulatory elements important for establishing subclasses of cells in the developing mouse cortex. The recent finding that genes involved in chromatin changes during learning and memory are known to be involved in brain development and associated with autism spectrum disorders 85 suggests that developmental regulatory elements harboring disease-associated polymorphisms may play a dual role in synaptic plasticity. Identifying and understanding the role of such regulatory elements during development could therefore improve our ability to characterize their roles in disease pathogenesis during adulthood.…”

Genome-wide profiling reveals functional diversification of ∆FosB gene targets in the hippocampus of an Alzheimer's disease mouse model

“…However, differences in the chromatin accessibility landscape of APP versus NTG neurons may also have a major impact on how ∆FosB interacts with the genome. Recent studies found that neuronal activity or behavioral training cause significant chromatin reorganization in hippocampal neurons [ 26 , 49 ]. Activity appears to largely induce chromatin relaxation at gene regions throughout the genome, allowing various IEG transcription factors such as cFos and FosB to access gene targets [ 26 ].…”

Myosin XVI in the Nervous System

“…The physiological relevance of Myo16 in neural functioning was assayed in animal studies [ 30 , 52 , 53 ]. In the triple KO mice for all the three NYAP proteins including Myo16/NYAP3 a reduction in brain size and weight was observed that may be indicative of neurite hypotrophy [ 30 ].…”

“…Behavioral analyses of MYO16 −/− mice revealed no phenotypes and dysfunctions in locomotor activity, motor learning and social interaction; behaviors altered in the mouse model of ASD. Although the epigenetic control of MYO16 was described upon experience-based learning (contextual fear conditioning) in mouse [ 53 ].…”