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Home arrow Health arrow DNA Modifications in the Brain. Neuroepigenetic Regulation of Gene Expression
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ROLE OF 5hmC IN BRAIN DEVELOPMENT

Across brain development in both human and mouse, 5hmC levels increase, with the adult human prefrontal cortex containing 10-fold more 5hmC than the fetal brain (Lister et al., 2013; Wen et al., 2014). In the adult (6-week-old mouse), high levels of 5hmC are found across enhancer, transcriptional end site, intragenic, and DHS regions. In the fetus, in contrast, enrichment of 5hmC is primarily in DHS regions and enhancer regions that are unique to fetal development (Lister et al., 2013). Many of the gene bodies that gain 5hmC enrichment in the adult stage also have 5hmC present at the fetal stage, albeit at much lower levels. This implies that the cell type-specific increase in 5hmC observed over development occurs at intragenic regions that were partially established at the fetal stage. Although 5hmC levels of the fetal brain are much lower than those of the adult brain across all genomic features, there are numerous CpGs in which hydroxymethyl- ation is higher in the fetal brain (fetal > adult hydroxymethylated CpGs).These fetal > adult hydroxymethylated CpGs are enriched at enhancers (Lister et al., 2013; Wen et al., 2014). Developmentally downregulated genes have high levels of gene body 5hmC at the fetal stage, but not at the adult stage (Lister et al., 2013). Regions that have significantly higher hydroxymethylation in the fetal frontal cortex than the adult are dormant regions poised for demethylation and activation over development in both the mouse and human (Lister et al., 2013; Wen et al., 2014). Analysis of these developmentally dependent, differentially hydroxymethylated regions in adult Tet2-/- mice revealed that these 5hmC-poised loci are dependent upon TET2 activity (Lister et al., 2013). These findings suggest a key role of 5hmC in brain development that is conserved across mammals.

5hmC marks both developmentally dependent [postnatal day 7 (P7), 6-week-old, and 1-year-old mice] and brain region-specific (hippocampus compared to cerebellum) loci. When brain region-specific differentially hydroxymethylated loci were evaluated across development, it was found that 5hmC marks region-specific genes during early development (at P7 or earlier) to facilitate in region-specific transcriptional programs. These tissue-specific differentially hydroxymethylated regions are enriched for a 21-nucleotide motif that might be critical for regulating specific gene expression programs. 5hmC-regulated regions across development within mouse cerebellum and hippocampus revealed that some loci are stable (5hmC acquired during P7 and maintained through 1 year of age), whereas others are dynamic (5hmC is not present at all time points). When repeat elements were assessed across development, it was found that, in both mouse hippocampus and cerebellum, 5hmC enrichment increases at short interspersed nuclear elements and long tandem repeats and decreases in long interspersed nuclear elements and satellites. In P7 cerebellum, but not adult, 5hmC is associated with the transcriptional start site (TSS) of genes with low expression. This can be explained by the fact that at this stage, a significant amount of progenitor cells are present, which is in line with the finding in mouse and human ESCs in which 5hmC is enriched at the TSS of repressed, but developmentally poised, genes. At developmentally activated genes, there is an increase in intragenic 5hmC, whereas at developmentally repressed genes, there is only a small decrease in 5hmC across the gene body (Szulwach et al., 2011). These findings highlight the importance of 5hmC in brain development.

 
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