Dissecting TET2 Regulatory Networks in Blood Differentiation and Cancer

Abstract

Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation can be either passive or active when initiated by TET dioxygenases. During active demethylation, transcription factors (TFs) recruit TET enzymes (TET1, 2, and 3) to specific gene regulatory regions to first catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and subsequently to higher oxidized cytosine derivatives. Only TET2 is frequently mutated in the hematopoietic system from the three TET family members. These mutations initially lead to the hematopoietic stem cells (HSCs) compartment expansion, eventually evolving to give rise to a wide range of blood malignancies. This review focuses on recent advances in characterizing the main TET2-mediated molecular mechanisms that activate aberrant transcriptional programs in blood cancer onset and development. In addition, we discuss some of the key outstanding questions in the field.

TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent manner

“…The cell specificity of TET mediated DNA demethylation can be attributed to transcription factors that interact with TET proteins and direct them to specific loci across the genome. Indeed, various interactions among TET proteins and transcription factors have been described (83), for instance during the process of B cell differentiation (15) and during reprogramming (13). In addition, inhibition of interaction of TET2 with Wilm's tumor gene (WT1) has been reported to promote tumorigenesis (12).…”

Immunopathogenesis and environmental triggers in coeliac disease

“… 7 8 In a substantial number of cases, this advantage is likely reinforced by LOF mutations in TNFAIP3/A20, a potent negative regulator of the nuclear factor kappa B pathway, which is activated by other inflammatory cytokines, such as tumor necrosis factor α or IL-1. 8 72 Importantly, RCD2 IEL carry many additional oncogenic mutations such as recurrent LOF mutations in the DNA methylase TET2 73 and in the histone-methyl-transferase KMT2D, 74 which may foster transformation and ultimately lead to invasive EATL 8 ( figure 4A ).…”

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…In contrast to DNMT3A, TET2 dioxygenase demethylates DNA by oxidizing 5-methylcytosine to 5-hydroxy-methylcytosine (see recent reviews [ 312 , 323 ]). Fluxes in substrates and cofactors provided by metabolic pathways or changes to glycolytic enzymes during aging influence TET2 enzymatic reactions [ 10 , 296 , 315 , 323 , 324 , 325 ], thereby altering DNA methylation patterns and subsequently HSPC fate.…”

“…In contrast to DNMT3A, TET2 dioxygenase demethylates DNA by oxidizing 5-methylcytosine to 5-hydroxy-methylcytosine (see recent reviews [ 312 , 323 ]). Fluxes in substrates and cofactors provided by metabolic pathways or changes to glycolytic enzymes during aging influence TET2 enzymatic reactions [ 10 , 296 , 315 , 323 , 324 , 325 ], thereby altering DNA methylation patterns and subsequently HSPC fate. TET2 catalytic activity, for example, is dependent on α-ketoglutarate, is activated by Fe ++ and ascorbate, and is inhibited by 2-hydroxyglutarate, fumarate and succinate, with increases in glycolysis limiting α-ketoglutarate availability and with upregulation of oxidative phosphorylation enhancing α-ketoglutarate levels [ 293 , 294 , 302 ].…”

“…TET2 catalytic activity, for example, is dependent on α-ketoglutarate, is activated by Fe ++ and ascorbate, and is inhibited by 2-hydroxyglutarate, fumarate and succinate, with increases in glycolysis limiting α-ketoglutarate availability and with upregulation of oxidative phosphorylation enhancing α-ketoglutarate levels [ 293 , 294 , 302 ]. TET2-deficient human or murine HSC clones exhibit enhanced proliferation and a myeloid bias [ 325 ], while single Tet2-/- murine HSCs demonstrate significant changes to DNA methylation of lineage specific transcription factor binding motifs, with resultant disruption to transcriptional priming [ 323 , 324 ]. TET2 loss-of-function mutations also increase secretion of proinflammatory cytokines by mutant TET2 hematopoietic cells, which can alter HSPC fitness and enhance clonal expansion [ 272 ].…”