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Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

ABSTRACT: During aging, blood cell production becomes dominated by a limited number of variant hematopoietic stem cell (HSC) clones. Differentiated progeny of variant HSCs are thought to mediate the detrimental effects of such clonal hematopoiesis on organismal health, but the mechanisms are poorly understood. While somatic mutations in DNA methyltransferase 3A (DNMT3A) frequently drive clonal dominance, the aging milieu also likely contributes. Here, we examined in mice the interaction between high-fat diet (HFD) and reduced DNMT3A in hematopoietic cells; strikingly, this combination led to weight gain. HFD amplified pro-inflammatory pathways and upregulated inflammation-associated genes in mutant cells along a pro-myeloid trajectory. Aberrant DNA methylation during myeloid differentiation and in response to HFD led to pro-inflammatory activation and maintenance of stemness genes. These findings suggest that reduced DNMT3A in hematopoietic cells contributes to weight gain, inflammation, and metabolic dysfunction, highlighting a role for DNMT3A loss in the development of metabolic disorders.

SUBMITTER: Reyes JM

PROVIDER: S-EPMC10897855 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

Reyes Jaime M JM Tovy Ayala A Zhang Linda L Bortoletto Angelina S AS Rosas Carina C Chen Chun-Wei CW Waldvogel Sarah M SM Guzman Anna G AG Aguilar Rogelio R Gupta Sinjini S Liu Ling L Buckley Matthew T MT Patel Kalyani R KR Marcogliese Andrea N AN Li Yumei Y Curry Choladda V CV Rando Thomas A TA Brunet Anne A Parchem Ronald J RJ Rau Rachel E RE Goodell Margaret A MA

iScience 20240205 3

During aging, blood cell production becomes dominated by a limited number of variant hematopoietic stem cell (HSC) clones. Differentiated progeny of variant HSCs are thought to mediate the detrimental effects of such clonal hematopoiesis on organismal health, but the mechanisms are poorly understood. While somatic mutations in <i>DNA methyltransferase 3A</i> (DNMT3A) frequently drive clonal dominance, the aging milieu also likely contributes. Here, we examined in mice the interaction between hig ...[more]

PMID: 38414863

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Dataset Information

Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

Publications

Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

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