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.

Exploring the epigenetic landscape: The role of 5-hydroxymethylcytosine in neurodevelopmental disorders

“…In a more recent paper by Papale et al ( 2022 ), the brain tissue of ASD mouse models ( Cntnap2 ) that were projected to prenatal stress was tested. The sample lacked behavioral or neuropathological abnormalities.…”

Prenatal stress unmasks behavioral phenotypes in genetic mouse models of neurodevelopmental disorders

“… Dams were exposed from GD 15–2 to a schedule of repeated variable stress, including restraint stress with or without light, and forced swim ( Ben Hamida et al, 2022 ). From GD 12–18, dams were exposed to variable stress, including constant lighting, restraint stress, exposure to fox odor, exposure to novel objects, exposure to novel noise, cage changes, and saturated bedding ( Papale et al, 2022 ). From GD 14–21, dams were exposed to a repeating schedule of restraint stress, wet bedding, cage changes, and exposure to novel objects ( Petroni et al, 2022a , b ).…”

“…From GD 12–18, dams were exposed to variable stress, including constant lighting, restraint stress, exposure to fox odor, exposure to novel objects, exposure to novel noise, cage changes, and saturated bedding ( Papale et al, 2022 ).…”

“…An additional concern is that individual variation in a dam’s response to stress can lead to litter effects, in which measures taken from pups within a specific litter correlate. One way to control for litter effects is by using only one to three offspring per litter for a particular study ( Schmidt et al, 2017 , 2022 ; Heslin and Coutellier, 2018 ; Papale et al, 2022 ). Alternatively, statistical methods are available that control for litter in the analyses ( Jiménez and Zylka, 2021 ).…”

Association of DNA methylation with energy and fear-related behaviors in canines

“…Gene by environment interactions have also been explored in rodent models. One study in mice found that Cntnap2 heterozygotes exposed to prenatal stress displayed altered sociability similar to Cntnap2 knockouts, indicating a gene by environment interaction in neurodevelopment disorders ( Papale et al, 2022 ). Another study examined genetic and environmental factors in impaired social and communication skills in mice, showing that the Nlgn3/Cyfip1 pathway plays a role in shaping behavior and is influenced by the social environment ( Sledziowska et al, 2020 ).…”