DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
Nature genetics, 2016•nature.com
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 …
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 …
Abstract
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.
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