DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells.
Academic Article
Overview
Research
Identity
Additional Document Info
View All
Overview
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.
published proceedings
Nat Genet
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
144
complete list of authors
Zhang, Xiaotian||Su, Jianzhong||Jeong, Mira||Ko, Myunggon||Huang, Yun||Park, Hyun Jung||Guzman, Anna||Lei, Yong||Huang, Yung-Hsin||Rao, Anjana||Li, Wei||Goodell, Margaret A