DNA Methylation in Neuronal Development and Disease

DNA methylation is an epigenetic modification that spatially and temporally regulates gene expression and has essential roles in controlling neuronal development and function. DNA methylation is generally associated with heterochromatin and repression of gene transcription. Methylated cytosine residues can also undergo demethylation by ten-eleven translocation (TET) enzymes, resulting in 5-hydroxymethylation and its downstream derivatives. Once thought of as an intermediary in the demethylation process, 5-hmC has been found to be a unique and stable epigenetic mark. 5-hmC is more highly enriched in mammalian brains than in other somatic cells, indicating its critical roles in the central nervous system. Unlike methylation, hydroxymethylation is usually associated with euchromatin and gene activation. Much progress has been made in the past few decades in defining the roles of methylation and hydroxymethylation, and their molecular machinery in the brain and nervous system. In this chapter, we provide a comprehensive review of the roles of methylation and hydroxymethylation in brain development, functions and their dysregulation in brain disorders. First, we discuss the current understanding of these epigenetic marks in normal neuronal development as well as brain function. DNA methylation and hydroxymethylation have also been implicated in the development and progression of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We discuss consistencies and inconsistencies of the available data in human, mouse and in vitro studies that link methylation and hydroxymethylation to neurodegeneration. Finally, we explore the potential of these neuronal epigenetic marks and their molecular machinery to provide novel therapeutic targets in neurodegenerative diseases.