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Nat Genet. 2016 Sep;48(9):1014-23. doi: 10.1038/ng.3610. Epub 2016 Jul 18.

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

Zhang X1,2,3, Su J4, Jeong M1,2, Ko M5,6, Huang Y7, Park HJ4, Guzman A1,2, Lei Y1,2, Huang YH1,2, Rao A5, Li W4, Goodell MA1,2,3.

Author information

1
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.
2
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
4
Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
5
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
6
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
7
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, USA.

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.

PMID:
27428748
PMCID:
PMC4957136
DOI:
10.1038/ng.3610
[Indexed for MEDLINE]
Free PMC Article

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