Keiko Iwata PhD, Kazuhiko Nakabayashi PhD, Keisuke Ishiwata PhD, Kazuhiko Nakamura MD, PhD, Yosuke Kameno MD, PhD, Kenichiro Hata MD, PhD, Hideo Matsuzaki MD, PhD
doi.org/10.1111/pcn.13830
Abstract
Aim
Autism spectrum disorder (ASD) has a strong genetic basis, yet its genetic complexities remain elusive. Current research highlights environmental factors and epigenetic processes, such as DNA methylation, as crucial in ASD development. This exploratory study addresses a gap in understanding epigenetic regulation in the dorsal raphe (DR)—a region regulating multiple neurotransmitters and implicated in ASD—by examining DNA methylation profiles in postmortem ASD and control brains.
Methods
We comprehensively analyzed genome-wide DNA methylation profiles in the DR brain region (seven controls and five ASD) using the Infinium HumanMethylation450 BeadChip (Illumina). Additionally, quantitative polymerase chain reaction was used to measure messenger RNA levels of differentially methylated genes in ASD (11 controls and six ASD).
Results
We identified differentially methylated regions (DMRs) between ASD and controls. These DMRs were located among various genomic regions, including promoters, gene bodies, and intergenic regions. Notably, we found hypermethylation in genes related to olfaction (e.g. OR2C3), which is regulated by serotonin. Additionally, we observed that the hypomethylation of promoter-associated CpG islands in RABGGTB, a gene related to autophagy and synaptic function, corresponded with its increased expression.
Conclusions
Our findings reveal extensive DNA methylation changes in critical genomic regions, shedding light on potential mechanisms underlying ASD. The identification of RABGGTB as a novel candidate gene, not listed in the SFARI database, underscores its significance and warrants further research to explore its role in ASD diagnosis. This study enhances our understanding of the epigenetic landscape in ASD, emphasizing the interplay between genetic and environmental factors in its pathophysiology.
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