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Learning Recapitulates Development at the Epigenetic Level Highlighting Regulatory Regions Relevant for Autism and Intellectual Disability
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder of high prevalence that clearly involves genetic risk factors. Most current approaches aimed at identifying genetic risk factors in ASD focus on genes. However, most human disease-associated variants are located in regulatory regions that control gene expression. As such, a great number of relevant ASD genetic variants likely lie within regulatory regions. Intellectual Disability (ID), which leads to learning impairments, is the most common ASD comorbidity and the strongest predictor of poor prognosis. The genetic basis and underlying molecular mechanisms shared between learning and ASD therefore hold insights into a key aspect of these disorder.
Epigenetic modifications and regulation of gene expression are necessary for learning. Functionally relevant regulatory regions are determined through epigenetic modifications that define where chromatin is accessible in the genome. The connection between ASD and ID must be determined at least in part by epigenetic modifications that can be measured through chromatin accessibility. Defining regulatory regions relevant to ASD based on learning dependent chromatin remodeling is an unexplored yet potentially fruitful target for investigation.
Objectives:
The goal of this study was to determine which regulatory regions are recruited during memory consolidation and investigate whether they could highlight non-coding regions with genetic links to ASD and ID.
Methods:
We used sonication of cross-linked chromatin followed by sequencing (Sono-seq) to define how learning affects chromatin accessibility genome-wide in mice. We developed a new bioinformatics tool (DEScan) to uncover regulatory regions that show statistically significant differences in chromatin accessibility following learning. We integrated our results with publicly available datasets from ENCODE and SFARI, to better define the relationship between learning regulated regions, mechanisms of epigenetic regulation and known ASD linked genes.
Results:
Our results show that learning increases chromatin accessibility in 2,365 regulatory regions genome-wide (FDR <0.05). These learning regulated regions are bivalent promoters associated with CpG islands and show a strong bias towards being accessible during development relative to adulthood (p<0.001). Enrichment for active histone marks (H3K9ac, H3K4me2/3) within learning regulated regions is also higher for embryonic than postnatal datasets (p<0.05). Thus, our data shows that learning increases chromatin accessibility of regulatory regions that are active during development. Learning regulated regions are also disproportionally associated with known ASD genes (SFARI, p< 0.01). The enrichment was found at any SFARI gene evidence level, and the fold enrichment was higher at lower SFARI scores. Learning regulated regions were associated with 15 forms of syndromic ASD that also present with ID.
Conclusions:
Overall our study suggests that the high comorbidity of ASD and ID could be based at least in part on the fact that learning relies on a subset of regulatory regions that are also required for brain development. We also show that using epigenomic data obtained in mice is a viable strategy to highlight functionally relevant regulatory regions to study the contribution of non-coding genetic variation to ASD. Future studies will focus on testing whether learning regulated regions harbor non-coding genetic variants associated with ASD and ID.