Gene by environment interaction mouse model reveals a functional role for 5-hydroxymethylcytosine in neurodevelopmental disorders
Abstract
Mouse knockouts of Cntnap2 exhibit altered neurodevelopmental behavior, deficits in striatal GABAergic signaling and a genome-wide disruption of an environmentally sensitive DNA methylation modification (5-hydroxymethylcytosine, 5hmC) in the orthologs of a significant number of genes implicated in human neurodevelopmental disorders. We tested adult Cntnap2 heterozygous mice (Cntnap2+/-, lacking behavioral or neuropathological abnormalities) subjected to a prenatal stress and found that prenatally stressed Cntnap2+/- female mice showed repetitive behaviors and altered sociability, similar to the homozygote phenotype. Genomic profiling revealed disruptions in hippocampal and striatal 5hmC levels that were correlated to altered transcript levels of genes linked to these phenotypes (e.g., Reln, Dst, Trio, and Epha5). Chromatin-immunoprecipitation coupled with high-throughput sequencing and hippocampal nuclear lysate pull-down data indicated that 5hmC abundance alters the binding of the transcription factor CLOCK in the promoters of these genes (e.g., Palld, Gigyf1, and Fry), providing a mechanistic role for 5hmC in gene regulation. Together, these data support gene by environment hypotheses for the origins of mental illness and provide a means to identify the elusive factors contributing to complex human diseases.
- Received August 23, 2021.
- Accepted December 22, 2021.
- Published by Cold Spring Harbor Laboratory Press
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