DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells

Margaret Goodell, Wei Li and colleagues use double-knockout mice for Dnmt3a and Tet2 to model leukemia development. Through epigenetic and transcriptional analyses, they show that loss of DNMT3A and TET2 upregulates lineage-specific transcription factors such as KLF1 in hematopoietic stem cells and accelerates malignancy. Mutations in the epigenetic modifiers DNMT3A and TET2 non-randomly co-occur in lymphoma and leukemia despite their epistasis in the methylation–hydroxymethylation pathway. Using Dnmt3a and Tet2 double-knockout mice in which the development of malignancy is accelerated, we show that the double-knockout methylome reflects regions of independent, competitive and cooperative activity. Expression of lineage-specific transcription factors, including the erythroid regulators Klf1 and Epor , is upregulated in double-knockout hematopoietic stem cells (HSCs). DNMT3A and TET2 both repress Klf1 , suggesting a model of cooperative inhibition by epigenetic modifiers. These data demonstrate a dual role for TET2 in promoting and inhibiting HSC differentiation, the loss of which, along with DNMT3A, obstructs differentiation, leading to transformation.