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

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.

altmetric score

  • 15.75

author list (cited authors)

  • Zhang, X., Su, J., Jeong, M., Ko, M., Huang, Y., Park, H. J., ... Goodell, M. A.

citation count

  • 126

publication date

  • July 2016