Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.

DNA Methyltransferase 3A / genetics Animals Atherosclerosis / genetics Dioxygenases Macrophages / metabolism DNA (Cytosine-5-)-Methyltransferases / genetics Phenotype Proto-Oncogene Proteins / genetics DNA-Binding Proteins / genetics Loss of Function Mutation Disease Models, Animal Mice, Inbred C57BL Mice, Knockout Male Aortic Diseases / genetics Mice Cytokines / metabolism Immunity, Innate / genetics Inflammation Mediators / metabolism Clonal Hematopoiesis / genetics Female

Journal

Nature cardiovascular research

ISSN: 2731-0590

Titre abrégé: Nat Cardiovasc Res

Pays: England

ID NLM: 9918284280206676

Informations de publication

Date de publication:
Sep 2023

Historique:

received: 06 10 2021

accepted: 27 07 2023

medline: 28 8 2024

pubmed: 28 8 2024

entrez: 28 8 2024

Statut: ppublish

Résumé

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.

Identifiants

DOI: 10.1038/s44161-023-00326-7 PMID: 39196062

pubmed: 39196062

doi: 10.1038/s44161-023-00326-7

pii: 10.1038/s44161-023-00326-7

doi:

Substances chimiques

DNA Methyltransferase 3A EC 2.1.1.37

Dioxygenases EC 1.13.11.-

DNA (Cytosine-5-)-Methyltransferases EC 2.1.1.37

Dnmt3a protein, mouse 0

Tet2 protein, mouse EC 1.13.11.-

Proto-Oncogene Proteins 0

DNA-Binding Proteins 0

Cytokines 0

Inflammation Mediators 0

DNMT3A protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

805-818

Subventions

Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)

ID : R01HL080472

Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)

ID : R01HL082945

Informations de copyright

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