Epigenetic Profiling Reveals Molecular Changes in Autism Brain

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects how the brain processes sensory information and social cues, often impairing social interactions. While genetic factors are well-studied, recent research highlights the important role of environmental influences and epigenetic mechanisms, such as DNA methylation, in ASD development. One brain region implicated in ASD is the dorsal raphe (DR), which is involved in serotonin signaling and is sensitive to immune activation and stress hormones. However, the DNA methylation patterns in the DR related to ASD have not been explored until now.

Investigating DNA methylation in the dorsal raphe

A research team in Japan led by Professor Hideo Matsuzaki at the Research Center for Child Mental Development, University of Fukui, in collaboration with Dr. Keiko Iwata from the School of Pharmaceutical Sciences, Wakayama Medical University, conducted an epigenetic analysis on postmortem brain samples from individuals with and without ASD. Their findings, published April 24, 2025 in Psychiatry and Clinical Neurosciences, represent the first study to profile genome-wide DNA methylation in the DR nucleus in relation to autism.

The team used the Infinium HumanMethylation450 BeadChip (Illumina) to assess DNA methylation, a process where chemical tags on DNA influence gene activity without altering the genetic code. They also applied quantitative reverse transcription polymerase chain reaction (qRT-PCR) to measure gene expression levels. To confirm site-specific DNA methylation changes, the researchers performed EM-amplicon sequencing.

Altered DNA methylation in key genes

The analysis revealed widespread DNA methylation abnormalities in genomic regions critical to brain function. Among the notable findings were hypermethylation (increased DNA methylation) of OR2C3, an olfactory receptor gene, and HTR2C, a serotonin receptor gene, in ASD samples. These changes may be related to sensory processing challenges and disruptions in serotonin signaling observed in ASD.

In contrast, the promoter region of RABGGTB, a gene involved in autophagy and synaptic function, showed hypomethylation (reduced DNA methylation) coupled with increased gene expression. This gene is not currently listed in the SFARI gene database, a key resource cataloguing autism-related genes, making it a novel candidate for further investigation.

Potential implications for autism research

The discovery of RABGGTB as a candidate gene offers new insights into the molecular pathways potentially involved in ASD. Further research into this gene may advance understanding of the disorder’s biological underpinnings and contribute to the development of future diagnostic biomarkers.

While this study provides important clues on how epigenetic alterations in the DR may influence ASD, additional work integrating DNA methylation data with transcriptome analyses will be necessary to clarify the relationship between epigenetic changes and gene expression in autism.

Reference: Iwata K, Nakabayashi K, Ishiwata K, et al. Genome‐wide DNA methylation profiles in the raphe nuclei of patients with autism spectrum disorder. Psychiatry Clin Neurosci. 2025:pcn.13830. doi: 10.1111/pcn.13830

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