Association between epigenetic mark 5-hydroxymethylcytosine and brain pathophysiology

Over the last decade, the identification of the sixth base, 5-hydroxymethylcytosine (5-hmC), and its emerging association with brain disorders have provided new insights into the pathophysiological implications of neuroepigenetic changes. This epigenetic modification occurs due to Ten-eleven translocase 1/2/3 (Tet1/2/3) mediated oxidation of 5-methylcytosine (5-mC) molecules, reversing the methyl-dependent silencing of genes and changing the genomic landscape within the cells, thereby altering downstream signaling cascades. 5-hmC is enriched in the brain tissues and is involved in neurogenesis and brain development. However, the exact functional significance of 5-hmC has not been fully explored. The level of 5-hmC is altered with age, environmental toxicity, hormonal imbalances, exposure to challenges like sleep loss, changes in the level of neurotransmitters, and mutations in the Tet enzymes, resulting in the onset, sensitization or predisposition to brain pathology. In this review, we have discussed the recent studies investigating the role of DNA hydroxymethylation in various neurological disorders. These findings suggest that 5-hmC may play a regulatory role in the aetiology of neurodevelopmental, neurodegenerative and neuropsychiatric disorders. We also propose a potential role of 5-hmC in neuronal disorders associated with REM sleep deprivation.