Abstract
Studies of tissue-specific epigenomes have revealed 5-hydroxymethylcytosine (5hmC) to be a highly enriched and dynamic DNA modification in the metazoan nervous system, inspiring interest in the function of this epigenetic mark in neurodevelopment and brain function. 5hmC is generated by oxidation of 5-methylcytosine (5mC), a process catalyzed by the ten–eleven translocation (TET) enzymes. 5hmC serves not only as an intermediate in DNA demethylation but also as a stable epigenetic mark. Here, we review the known functions of 5hmC and TET enzymes in neural progenitor cell biology and embryonic and postnatal neurogenesis. We also discuss how TET enzymes and 5hmC regulate neuronal activity and brain function and highlight their implications in human neurodevelopmental and neurodegenerative disorders. Finally, we present outstanding questions in the field and envision new research directions into the roles of 5hmC and TET enzymes in neurodevelopment.
Highlights
Precise temporal and spatial control of gene expression is essential for metazoan neurogenesis
Cortical 5hmC has cell-type specific distributions associated with differential gene expression (Kozlenkov et al, 2018), and the ability of ten–eleven translocation (TET) to promote active DNA demethylation and alter gene expression in response to neuronal activity and to influence behavior has been the subject of extensive study (Guo et al, 2011; Kaas et al, 2013; Rudenko et al, 2013; Zhang et al, 2013; Li et al, 2014; Yu et al, 2015)
A dozen years since the discovery that TET enzymes promote DNA hydroxylation and demethylation and the first studies reporting the abundance of 5hmC in the mammalian nervous system (Kriaucionis and Heintz, 2009; Tahiliani et al, 2009), work in the field has shed some light on their functions in neural physiology
Summary
Precise temporal and spatial control of gene expression is essential for metazoan neurogenesis. To understand the roles of 5hmC and TETs in regulation of neural gene expression, several studies have mapped the genomic distribution of 5hmC in various neural cell types and tissues over the course of embryonic and postnatal development (Jin et al, 2011; Szulwach et al, 2011; Khare et al, 2012; Hahn et al, 2013; Lister et al, 2013).
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