Tet family proteins and 5-hydroxymethylcytosine in development and disease

Abstract

SummaryOver the past few decades, DNA methylation at the 5-position of cytosine (5-methylcytosine, 5mC) has emerged as an important epigenetic modification that plays essential roles in development, aging and disease. However, the mechanisms controlling 5mC dynamics remain elusive. Recent studies have shown that ten-eleven translocation (Tet) proteins can catalyze 5mC oxidation and generate 5mC derivatives, including 5-hydroxymethylcytosine (5hmC). The exciting discovery of these novel 5mC derivatives has begun to shed light on the dynamic nature of 5mC, and emerging evidence has shown that Tet family proteins and 5hmC are involved in normal development as well as in many diseases. In this Primer we provide an overview of the role of Tet family proteins and 5hmC in development and cancer.

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

“…However, in contrast to Tet1, the Tet3 CXXC binding domain recognizes unmodified C followed by A, T, C, or G, with a preference for nonpromoter CpGs (51). Moreover, Tet3 also contains the novel-binding domain PRK12323, the function of which has not been determined (52). Tet3 is also endowed with a function that is independent of its enzymatic activity: Tet3 is a direct binding partner with O-linked N-acetylglucosamine transferase and colocalizes with this transferase on chromatin at active promoters enriched for H3K4 me3 , which is critically involved in transcriptional activation (53,54).…”

MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation

“…For example, the expression of pancreatic and duodenal homeobox 1 (Pdx1) in embryonic foregut region induces pancreas commitment (19,20), and those early progenitor cells have the potential to give rise to all three pancreatic lineages (21,22). Subsequent activation of another transcription factor, neurogenin 3 (Ngn3), restricts the lineage potential to endocrine cells (21, 23).Expression of TETs and the genomic content of 5hmC vary across tissues (13,14). Interestingly, TET2 and TET3 are highly expressed in the murine adult pancreas (2), yet the pancreas has lower genomic 5hmC levels than other adult tissues derived from endoderm, including liver and lung (4), suggesting dynamic DNA demethylation during pancreas development.…”

“…Expression of TETs and the genomic content of 5hmC vary across tissues (13,14). Interestingly, TET2 and TET3 are highly expressed in the murine adult pancreas (2), yet the pancreas has lower genomic 5hmC levels than other adult tissues derived from endoderm, including liver and lung (4), suggesting dynamic DNA demethylation during pancreas development.…”

“…Despite these advances, the molecular mechanisms underlying TETs/ TDG regulation are still not known. In addition, although recent data suggest a role of TET and 5hmC in embryonic stem cells and primordial germ cells (2,(7)(8)(9)(10)(11)(12), evidence for enzymatic demethylation by TET enzymes during differentiation of cells of later stages, such as the postnatal and adult stem cells of various organs including pancreas, remains very limited (13)(14)(15)(16).…”

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

“…TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), which is required for subsequent DNA demethylation. 27 TET proteins are thought to have a role in tumor development, as inhibition of TET activity, as well as alteration of global DNA methylation, has been demonstrated in multiple tumor types. [28][29][30][31][32] Thus, succinate accumulation in the context of SDH deficiency could potentially drive tumorigenesis via the inhibition of TET family proteins and subsequent changes in DNA methylation and gene expression patterns.…”