Dynamics of ten‐eleven translocation hydroxylase family proteins and 5‐hydroxymethylcytosine in oligodendrocyte differentiation

Abstract

The ten-eleven translocation (TET) family of methylcytosine dioxygenases catalyze oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promote DNA demethylation. Despite the abundance of 5hmC and TET proteins in the brain, little is known about their role in oligodendrocytes (OLs). Here, we analyzed TET expression during OL development in vivo and in vitro, and found that three TET family members possess unique subcellular and temporal expression patterns. Furthermore, the level of 5hmC exhibits dynamic changes during OL maturation, which implies that 5hmC modification may play a role in the expression of critical genes necessary for OL maturation. siRNA-mediated silencing of the TET family proteins in OLs demonstrated that each of the TET proteins is required for OL differentiation. However, based on their unique domain structures, we speculate that the three TET members may function by different mechanisms. In summary, we have established the temporal expression of TET proteins and the dynamic level of 5hmC during OL development and demonstrate that all three TET members are necessary for OL differentiation.

White matter tract and glial-associated changes in 5-hydroxymethylcytosine following chronic cerebral hypoperfusion

“…Additionally, we observed dynamic changes in TET protein levels with oligodendroglial maturation and oxidative stress in vitro, suggesting important developmental and environment-dependent epigenetic alterations in these cells. Similar results were observed in vivo where alterations in TET1, TET2, and TET3 proteins accompanied oligodendroglial maturation in the developing CNS (Zhao et al, 2014). Differences between OPCs and mature oligodendrocytes were reported for other epigenetic marks such as HDAC1-a known repressor of transcriptional activation (Liu and Casaccia, 2010) which is increased in the mature cells and associated with their more compact chromatin structure.…”

“…Additionally, oligodendrocytes constituting the myelin sheet also exhibit dynamic age-related changes in their epigenome. TET proteins catalyzing the conversion of 5mC to 5hmC show dynamic alterations during oligodendroglial maturation in the developing CNS (Zhao et al, 2014). Furthermore, at the difference from their progenitor cells, mature oligodendrocytes usually present compact chromatin structure and increased histone deacetylase 1 (HDAC1) expression (Liu and Casaccia, 2010).…”

Epigenetic control of oligodendrocyte development: adding new players to old keepers

“…Dynamic expressions of DNA methyltransferases and ten-eleven translocation enzymes (TETs) in the oligodendroglial lineage suggested that DNA methylation and hydroxymethylation are essential for oligodendrocyte differentiation [17,18]. Indeed, TET1, TET2, and TET3 have been shown to be necessary for oligodendrocyte differentiation in vitro [18]. Recently, a whole-genome transcriptome and methylome analysis comparing OPCs and oligodendrocytes revealed that DNA methylation is inversely correlated with gene expression during developmental myelination.…”

DNA methylation in fibrosis

“…The ten-eleven translocation (TET) family of proteins are responsible for the oxidation of 5mC into 5-hydroxymethylcytosine (5hmC) (Zhao et al, 2014), and whilst 5mC is typically associated with gene silencing effects, 5hmC is associated with an increase in gene expression (Coppieters et al, 2014). In addition, it has been found that TET can also covert 5mC into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (Ito et al, 2011).…”