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

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.

authors

• Huang, Yun

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

publisher

• Springer Science and Business Media LLC  Publisher

published in

• Nat Genet  Journal

keywords

• Animals
• Cell Differentiation
• Cell Lineage
• Cell Transformation, Neoplastic
• Cells, Cultured
• DNA Methylation
• DNA-Binding Proteins
• Dna (cytosine-5-)-methyltransferases
• Gene Expression Regulation
• Hematopoietic Stem Cells
• Kruppel-Like Transcription Factors
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins
• Receptors, Erythropoietin

PubMed Central ID

• 27428748

Digital Object Identifier (DOI)

• 10.1038/ng.3610

start page

• 1014

end page

• 1023

volume

• 48

issue

• 9