Portal de Periódicos da CAPES

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

2016; Nature Portfolio; Volume: 48; Issue: 9 Linguagem: Inglês

10.1038/ng.3610

1546-1718

Xiaotian Zhang, Jianzhong Su, Mira Jeong, Myunggon Ko, Yun Huang, Hyun Jung Park, Anna Guzman, Yong Lei, Yung‐Hsin Huang, Anjana Rao, Wei Li, Margaret A. Goodell,

Genetic Syndromes and Imprinting

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.