title: DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells.
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.affiliation: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.|Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Su
authors.affiliation: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.|Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Mira
authors.initials: M
authors.lastname: Jeong
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
authors.forename: Myunggon
authors.initials: M
authors.lastname: Ko
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.|Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Guzman
authors.affiliation: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.|Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.|Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Huang
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wei
authors.identifier: 0000-0001-9931-5990
authors.initials: W
authors.lastname: Li
authors.affiliation: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.|Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Margaret A
authors.identifier: 0000-0003-1111-2932
authors.initials: MA
authors.lastname: Goodell
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000502:physiology*; D049308:Dioxygenases; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D017467:Receptors, Erythropoietin / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; C080774:erythroid Kruppel-like factor; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A