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

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...

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Published in:iScience 2024-03, Vol.27 (3), p.109122, Article 109122
Main Authors: Reyes, Jaime M., Tovy, Ayala, Zhang, Linda, Bortoletto, Angelina S., Rosas, Carina, Chen, Chun-Wei, Waldvogel, Sarah M., Guzman, Anna G., Aguilar, Rogelio, Gupta, Sinjini, Liu, Ling, Buckley, Matthew T., Patel, Kalyani R., Marcogliese, Andrea N., Li, Yumei, Curry, Choladda V., Rando, Thomas A., Brunet, Anne, Parchem, Ronald J., Rau, Rachel E., Goodell, Margaret A.
Format: Article
Language:English
Subjects:
Epigenetics
Immunology
Physiology
Stem cells research
Transcriptomics
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Summary: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. [Display omitted] •DNMT3A loss in the blood combined with high-fat diet may accelerate weight gain•High-fat diet increases DNMT3A-mutant macrophages in adipose and pancreas tissue•DNMT3A establishes DNA methylation during macrophage differentiation from HSCs•Loss of DNMT3A leads to activated inflammatory pathways in HSCs and their progeny Physiology; Epigenetics; Immunology; Stem cells research; Transcriptomics
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.109122