Tet2

I n this issue of Circulation, Potus et al 1 describe a genetic association of the TET2 gene (TET methylcytosine dioxygenase 2) with idiopathic pulmonary arterial hypertension (PAH) and PAH associated with connective tissue diseases (CTD-PAH) by showing an increased rate of loss-of-function variants in patients with PAH and CTD-PAH compared with control subjects.Circulating TET2 expression was also decreased in patients with PAH independent of their mutation status for TET2.These results are supported by a model of conditional Tet2 knockout mice that develop spontaneous PAH with increased inflammation and vascular remodeling.The TET2 gene has been implicated in clonal hematopoiesis of indeterminate potential, observed primarily in older persons and defined by an expanded hematopoietic cell clone.These clones frequently carry acquired loss-of-function mutations of the TET2 gene or mutations in other genes involved in epigenetic regulation.The mutated stem cell clone has a selective advantage and can differentiate into circulating granulocytes, monocytes, and lymphocytes.In addition to an increased risk of hematologic cancers, clonal hematopoiesis of indeterminate potential is associated with increased risk of death and coronary heart disease and a 4-fold increased risk of myocardial infarction.2,3 The pathophysiology of the increased risk for coronary heart disease was studied in a model of irradiated atherosclerosis-prone mice that received a graft of hematopoietic cells from mice homozygous for Tet2 conditional loss of function.These mice developed more atherosclerotic lesions than did mice that received bone marrow from control mice.In mice deficient for Tet2 in the myeloid lineage only, cultured bone marrow macrophages manifested upregulated cytokines or chemokines and receptors.3 A similar experiment by Fuster et al 4 showed that Tet2-deficient macrophages exhibited an increase in NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome-mediated interleukin-1β secretion.Similarly, plasma interleukin-8, a CXC chemokine absent in mice, was increased in human subjects with TET2 mutations.3 These data suggest that TET2 acts as a negative transcriptional regulator of proinflammatory responses.The TET2 gene encodes an epigenetic modifier enzyme that mediates DNA demethylation.5 DNA methylation usually occurs at clusters of CpG dinucleotides called CpG islands, generally in promoter regions.Methylation is most often associated with the transcriptional inactivation of the affected gene.TET2 also acts by histone deacetylation to repress interleukin-6 transcription and other inflammatory mediators in dendritic cells and macrophages.6 Involvement of epigenetic mechanisms that modulate gene expression through DNA methylation, histone posttranslational modifications, and noncoding RNA (microRNA and long noncoding RNAs) has been investigated in PAH.Endothelial