Decoding the role of TET family dioxygenases in lineage specification

Abstract

Since the discovery of methylcytosine oxidase ten-eleven translocation (TET) proteins, we have witnessed an exponential increase in studies examining their roles in epigenetic regulation. TET family proteins catalyze the sequential oxidation of 5-methylcytosine (5mC) to oxidized methylcytosines including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine. TETs contribute to the regulation of lineage-specific gene expression via modulating DNA 5mC/5hmC balances at the proximal and distal regulatory elements of cell identity genes, and therefore enhance chromatin accessibility and gene transcription. Emerging evidence suggests that TET dioxygenases participate in the establishment and/or maintenance of hypomethylated bivalent domains at multiple differentiation-associated genes, and thus ensure developmental plasticity. Here, we review the current state of knowledge concerning TET family proteins, DNA hydroxymethylation, their distribution, and function in endoderm, mesoderm, and neuroectoderm specification. We will summarize the evidence pertaining to their crucial regulatory roles in lineage commitment and development.

Keywords: 5hmC; 5mC; Bivalent promoter; Enhancer; Lineage specification; TET.

Fig. 1

The role of TET proteins on lineage-specific bivalent promoters and enhancers. a In the presence of TET dioxygenases, PRC2 recruits TETs to bivalent promoters to maintain their hypomethylated status. In the absence of TETs, binding of DNMT3B at the bivalent promoters causes de novo DNA methylation, which leads to stable gene silencing and loss of developmental plasticity. b A model of TET-mediated enhancer priming and activation. Upon differentiation, pioneer transcription factors that are not sensitive to DNA modifications can bind to distal enhancers of lineage-specific genes and recruit TETs to demethylate methylcytosines. Other epigenetic modifiers, such as p300 and SET1/COMPASS, subsequently bind to these sites and establish poised (H3K4me1) and active (H3K27ac) enhancers, which in turn increases chromatin accessibility and allow other transcription factors binding to occur