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Cited by 258Acute Myeloid Leukemia ResearchEpigenetics and DNA MethylationHematopoietic Stem Cell Transplantation

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

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Zhang, Xiaotian, Su, Jianzhong, Jeong, Mira, Ko, Myunggon, Huang, Yun, Park, Hyun Jung, Guzman, Anna, Lei, Yong +4 more·2016·Nature Genetics
DOI 10.1038/ng.3610PMC PMC4957136
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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.

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  • Combined loss of Tet2 and Dnmt3A or presence of AML-associated gene lesions impairing myeloid cell maturation triggers malignant transformation of Tet2-deficient mouse HSC.

    “Only combined loss of Tet2 and Dnmt3A (18) or presence of AML-associated gene lesions impairing myeloid cell maturation triggers malignant transformation of Tet2-deficient mouse HSC (13).”

    From PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i> -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [18]

    The Results section reports that combined Dnmt3a and Tet2 loss produced earlier hematologic disease and a synergistic increase in malignancies, supporting the combined-loss part of the claim. But the paper does not establish that combined loss is the only route to malignant transformation; its Introduction also describes malignancies associated with loss of either gene. The AML-associated-lesions clause is attached to a different citation and is not judged here. Page numbers were not supplied. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • ARCH-associated mutations leading to perturbation of key regulators of DNA methylation, such as TET2 and DNMT3A, alter DNA methylation in a highly locus-specific fashion.

    “Past work has demonstrated that ARCH-associated mutations leading to perturbation of key regulators of DNA methylation, such as TET2 and DNMT3A, alter DNA methylation in a highly locus-specific fashion (18, 45).”

    From PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i> -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [18]

    The Introduction says DNMT3A and TET2 mutations are common in age-associated clonal hematopoiesis. The Results (‘DNMT3A and TET2 maintain DNA methylation in HSCs’; page unavailable) identify genotype-specific differentially methylated regions, supporting locus-specific effects. However, those methylation results come from knockout mouse HSCs, not from cells carrying ARCH-associated mutations. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • CH-associated variants of Dnmt3a and Tet2 affect the HSPC methylome and have been shown to alter functions of monocyte-derived tissue macrophages and promote cardiovascular pathologies.

    “CH-associated variants of the epigenetic writers and erasers Dnmt3a and Tet2, respectively, that affect the HSPC methylome have been shown to alter functions of monocyte-derived tissue M F and promote cardiovascular pathologies 31-34 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [31]

    The Introduction and the Results section on DNA methylation in HSCs support that DNMT3A and TET2 mutations occur in clonal hematopoiesis and that loss of these genes changes HSC methylation. The paper does not show altered functions of monocyte-derived tissue macrophages or promotion of cardiovascular pathology; its disease findings concern hematologic disease (Results, “Tet2 and Dnmt3a loss induces myeloid and lymphoid disease”; page numbers unavailable). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Emerging evidence suggests that cardiovascular pathologies and atherosclerosis exacerbated by CH mutation-afflicted MoMF involve distinct effector molecules, such as Il1b and IL6.

    “Emerging evidence suggests that cardiovascular pathologies and atherosclerosis exacerbated by CH mutation-afflicted MoM F involve distinct effector molecules, such as Il1 b and IL6 31,74 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [31]

    The Results and Discussion passages address DNMT3A/TET2 loss in hematopoietic stem cells and its relationship to lineage-gene expression and malignancy, not cardiovascular disease or atherosclerosis. Searches for cardiovascular pathology, macrophages, IL1b, and IL6 found no passage linking these molecules to CH-driven vascular disease; IL6 appears only as a component of cell-culture medium. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Zhang, X., Su, J., Jeong, M., Ko, M., Huang, Y., Park, H. J., Guzman, A., Lei, Y., Huang, Y.-H., Rao, A., Li, W., & Goodell, M. A.
Affiliations
  • Baylor College of Medicine (US)
  • La Jolla Institute for Immunology (US)
  • Texas A&M Health Science Center (US)
Corresponding author
  • Li, Wei
  • Goodell, Margaret A
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2016-07-18
Volume
48
Issue
9
Pages
1014-1023
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3610
PMC
PMC4957136
OpenAlex
W2498404744
Cited by
258
References
12
Citations by year
2026: 12 · 2025: 24 · 2024: 23 · 2023: 27 · 2022: 29 · 2021: 29 · 2020: 36 · 2019: 27 · 2018: 24 · 2017: 22 · 2016: 5
FWCI
24.74
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
Funders
  • Wellcome Trust
  • National Institutes of Health
  • National Human Genome Research Institute (R01HG007538)
  • National Cancer Institute (R01CA151535, R01CA183252, R01CA193466, R35CA210043, P30CA125123, P50CA126752)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R56DK092883, R01DK092883)
  • National Center for Research Resources (S10RR027366)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Keywords
DNMT3A, TET2, hematopoietic stem cells, lineage-specific transcription factors, KLF1, EPO receptor, DNA methylation, 5-hydroxymethylcytosine, epigenetic regulators, leukemia, lymphoma, HSC differentiation, epistasis, double knockout mice, epigenetic reprogramming
MeSH terms
DNA Methyltransferase 3A, Animals, Cell Differentiation, Cell Transformation, Neoplastic, Cells, Cultured, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Gene Expression Regulation, Hematopoietic Stem Cells, Proto-Oncogene Proteins, Receptors, Erythropoietin, Mice, Knockout, Cell Lineage, DNA Methylation, Dioxygenases, Mice, Kruppel-Like Transcription Factors

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