Hematologic DNMT3A Reduction and High-Fat Diet Synergize To Promote Weight Gain and Tissue Inflammation

Authors

Jaime M Reyes
Ayala Tovy
Linda Zhang
Angelina S Bortoletto
Carina Rosas
Chun-Wei Chen
Sarah M Waldvogel
Anna G Guzman
Rogelio Aguilar
Sinjini Gupta
Ling Liu
Matthew T Buckley
Kalyani R Patel
Andrea N Marcogliese
Yumei Li
Choladda V Curry
Thomas A Rando
Anne Brunet
Ronald J Parchem
Rachel E Rau
Margaret A Goodell

Publication Date

3-15-2024

Journal

iScience

DOI

10.1016/j.isci.2024.109122

PMID

38414863

PMCID

PMC10897855

PubMedCentral® Posted Date

2-5-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Physiology, Epigenetics, Immunology, Stem cells research, Transcriptomics

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.

Comments

This article has been corrected. See iScience. 2024 Jun 24;27(7):110313.

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