Emerging Roles for DNA 6mA and RNA m6A Methylation in Mammalian Genome.

Epigenetic methylation has been shown to play an important role in transcriptional regulation and disease pathogenesis. Recent advancements in detection techniques have identified DNA N6-methyldeoxyadenosine (6mA) and RNA N6-methyladenosine (m6A) as methylation modifications at the sixth position of adenine in DNA and RNA, respectively. While the distributions and functions of 6mA and m6A have been extensively studied in prokaryotes, their roles in the mammalian brain, where they are enriched, are still not fully understood. In this review, we provide a comprehensive summary of the current research progress on 6mA and m6A, as well as their associated writers, erasers, and readers at both DNA and RNA levels. Specifically, we focus on the potential roles of 6mA and m6A in the fundamental biological pathways of the mammalian genome and highlight the significant regulatory functions of 6mA in neurodegenerative diseases.

Dynamic Regulation of DNA Methylation and Brain Functions.

DNA cytosine methylation is a principal epigenetic mechanism underlying transcription during development and aging. Growing evidence suggests that DNA methylation plays a critical role in brain function, including neurogenesis, neuronal differentiation, synaptogenesis, learning, and memory. However, the mechanisms underlying aberrant DNA methylation in neurodegenerative diseases remain unclear. In this review, we provide an overview of the contribution of 5-methycytosine (5mC) and 5-hydroxylcytosine (5hmC) to brain development and aging, with a focus on the roles of dynamic 5mC and 5hmC changes in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Identification of aberrant DNA methylation sites could provide potential candidates for epigenetic-based diagnostic and therapeutic strategies for neurodegenerative diseases.

Brain Region- and Age-Dependent 5-Hydroxymethylcytosine Activity in the Non-Human Primate.

Because of the difficulty in collecting fresh brains of humans at different ages, it remains unknown how epigenetic regulation occurs in the primate brains during aging. In the present study, we examined the genomic distribution of 5hmC, an indicator of DNA methylation, in the brain regions of non-human primates (rhesus monkey) at the ages of 2 (juvenile), 8 (young adult), and 17 (old) years. We found that genomic 5hmC distribution was accumulated in the monkey brain as age increased and displayed unique patterns in the cerebellum and striatum in an age-dependent manner. We also observed a correlation between differentially hydroxymethylated regions (DhMRs) and genes that contribute to brain region-related functions and diseases. Our studies revealed, for the first time, the brain-region and age-dependent 5hmC modifications in the non-human primate and the association of these 5hmC modifications with brain region-specific function and potentially aging-related brain diseases.