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The autism spectrum disorders (ASD) comprise a broad group of behaviorally related neurodevelopmental disorders affecting as many as 1 in 68 children. The hallmarks of ASD consist of impaired social and communication interactions, pronounced repetitive behaviors and restricted patterns of interests. Family, twin and epidemiological studies suggest a polygenetic and epistatic susceptibility model involving the interaction of many genes; however, the etiology of ASD is likely to be complex and include both epigenetic and environmental factors. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Here, we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate a genome-wide profile of striatal 5hmC in an autism mouse model ( Cntnap2  −/−  mice) and found that at 9 weeks of age the  Cntnap2  −/−  mice have a genome-wide disruption in 5hmC, primarily in genic regions and repetitive elements. Annotation of differentially hydroxymethylated regions (DhMRs) to genes revealed a significant overlap with known ASD genes (e.g.  Nrxn1  and  Reln ) that carried an enrichment of neuronal ontological functions, including axonogenesis and neuron projection morphogenesis. Finally, sequence motif predictions identified associations with transcription factors that have a high correlation with important genes in neuronal developmental and functional pathways. Together, our data implicate a role for 5hmC-mediated epigenetic modulation in the pathogenesis of autism and represent a critical step toward understanding the genome-wide molecular consequence of the  Cntnap2  mutation, which results in an autism-like phenotype.

Genome-wide disruption of 5-hydroxymethylcytosine in a mouse model of autism