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Home arrow Health arrow DNA Modifications in the Brain. Neuroepigenetic Regulation of Gene Expression
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hmC CHANGES ASSOCIATED WITH NEURONAL DIFFERENTIATION

In addition to developmentally dependent changes in 5hmC, alterations in this epigenetic mark also occur across neuronal differentiation as assessed by comparing the genomic distribution of 5hmC in neural progenitor cells (NPCs) in the subventricular zone to that of maturing neurons of the cortical plate in embryonic day 15.5 mice. In NPCs and maturing neurons alike, there is an absence of 5hmC at enhancers and enrichment at promoters and gene bodies. Over differentiation there is an increase in 5hmC (but not 5mC), which is primarily intragenic. As typically found, intragenic 5hmC correlates transcription in both progenitors and mature neurons; however, this association is more pronounced in maturing neurons. Genes that gain intragenic 5hmC are associated with neuronal differentiation and axonogenesis. Genes with the highest increase in 5hmC over differentiation did not show an increase in demethylation, indicating the stability of this epigenetic mark. Concomitant with the increase in intragenic 5hmC during neuronal differentiation at activated genes is a gain of H3K4me3 at the promoter and a loss of H3K27me3 in gene bodies and promoters. TET2 or TET3 may play a role in neurogenesis since knockdown of their expression via electroporation of small hairpin RNAs (shRNAs) lead to defects in the progression of differentiation (Hahn et al., 2013).

Similar changes in 5hmC over neuronal differentiation also occurs in the olfactory sensory neuron (OSN) differentiation as there is an increase in 5hmC from the horizontal basal cell stage to the globose basal cell to mature olfactory sensory neurons (mOSNs).

Similar to neuronal differentiation in the ventricular zone, the increase in 5hmC across OSN differentiation is primarily intragenic and associated with developmentally regulated genes. When Tet3 is overexpressed in mOSNs via a transgenic mouse model approach, genes with modest levels of 5hmC in the wild-type (WT) mice exhibit an increase in 5hmC levels, and subsequent increase in expression, whereas genes with high levels of 5hmC exhibit a loss of 5hmC, and subsequent decrease in expression. The downregulation of the most highly expressed mOSN-specific genes, such as olfactory receptors and guidance molecules, affects glomerular formation (Colquitt et al., 2013). These findings from two neurogenic regions of the brain support the role of 5hmC in neuronal differentiation.

 
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