TET2: A Novel Epigenetic Regulator and Potential Intervention Target for Atherosclerosis

Abstract

Atherosclerosis is the underlying cause of cardio-cerebrovascular disease. However, the mechanisms of atherosclerosis are still unclear. The modification of DNA methylation has an important role in atherosclerosis development. As a member of the Ten-eleven translocation (TET) family, TET methylcytosine dioxygenase 2 (TET2) can modify DNA methylation by catalyzing 5-methylcytosine to 5-hydroxymethylcytosine and mediate DNA demethylation. Recent findings suggest that TET2 is related to the phenotype transformation of vascular smooth muscle cells, endothelial dysfunction, and inflammation of macrophage, the key factors of atherosclerosis. Therefore, TET2 may be a potential target for atherosclerosis treatment. This review will elaborate the recent findings that suggest the role of TET2 in atherosclerosis.

Keywords: DNA demethylation; TET2; atherosclerosis; inflammation.

FIG. 1.

Schematic of TET2 signaling pathways involved in AS. TET2 as a potential target for regulation of AS processes, including the transformation of smooth muscle cells, autophagy of endothelial cells, endothelial dysfunction, and chronic inflammation. In addition, it is presumed that TET2 may indirectly regulate the development of AS by regulating the genes related to AS-related diseases. The dotted line represents the results to be verified, and the solid line represents the confirmed conclusion. AS, atherosclerosis; TET2, Ten-Eleven translocation methylcytosine dioxygenase 2.

FIG. 2.

Factors involved in regulation of TET2 gene expression and enzyme activity. Transcription factors (NFYB, C/EBPα, Oct4) regulate TET2 mRNA levels in various developmental stages or cell types. microRNA inhibited TET protein expression in post-transcription level. TET protein can also be regulated by O-linked N-acetylglucosamine transferase or cullin-RING ubiquitin ligase 4-CRL4VprBP, acetyltransferase p300 in post-transcription level. IDAX results in TET2 protein degradation through caspase activation. Vitamin C acts as a cofactor for Fe2⁺ and 2-OG-dependent TET dioxygenase and can directly enhance the catalytic activity of TET protein. Pathological accumulation of three metabolites, namely, 2-hydroxyglutarete (2-HG), succinate, and fumarate, which are structurally similar to α-OG, leading to a competitive inhibition of α-OG-dependent TET activity. NFYB, nuclear transcriptional factor Y subunit beta.