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

Abstract

Recent advances in genetic and epigenetic research have underscored the significance of 5-hydroxymethylcytosine (5hmC) in neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and intellectual disability (ID), revealing its potential as both a biomarker for early detection and a target for novel therapeutic strategies. This review article provides a comprehensive analysis of the role of 5hmC in NDDs by examining both animal models and human studies. By examining mouse models, studies have demonstrated that prenatal environmental challenges, such as maternal infection and food allergies, lead to significant epigenetic alterations in 5hmC levels, which were associated with NDDs in offspring, impacting social behavior, cognitive abilities and increasing ASD-like symptoms. In human studies, researchers have linked alterations in 5hmC levels NDDs through studies in individuals with ASD, fragile X syndrome, TET3 deficiency and ID, specifically identifying significant epigenetic modifications in genes such as GAD1, RELN, FMR1 and EN-2, suggesting that dysregulation of 5hmC played a critical role in the pathogenesis of these disorders and highlighted the potential for targeted therapeutic interventions. Moreover, we explore the implications of these findings for the development of epigenetic therapies aimed at modulating 5hmC levels. The review concludes with a discussion on future directions for research in this field, such as machine learning, emphasizing the need for further studies to elucidate the complex mechanisms underlying NDDs and to translate these findings into clinical practice. This paper not only advances our understanding of the epigenetic landscape of NDDs but also opens up new avenues for diagnosis and treatment, offering hope for individuals affected by these conditions.

Keywords: 5-hydroxymethylcytosine; DNA methylation; autism; epigenetics; neurodevelopment; precision psychiatry.

Graphical abstract

Figure 1.

The DNA methyltransferase (DNMT) family of enzymes, DNMT1, DNMT3A and DNMT3B, catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the 5′ carbon of cytosine (C), resulting in 5-methylcytosine (5mC) (marker of gene repression). 5mC is converted back to cytosine by two possible mechanisms. One mechanism is the conversion of 5mC to 5hmC (variable marker of gene activation or repression) by the ten-eleven translocation methylcytosine dioxygenases (TET). 5hmC may then be converted to cytosine via subsequent enzymatic steps. A second possible mechanism involves a series of DNA replications or passive demethylation that, likely with decreased DNMT1 levels, fail to reproduce the methylation state of cytosine. Adapted from Khoodoruth and Khoodoruth (2024).

Figure 2.

Flow Chart of Included and Excluded Studies.