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

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 Rando; Anne Brunet; Ronald J Parchem; Rachel E Rau; Margaret A Goodell

doi:10.1016/j.isci.2024.109122

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

iScience. 2024 Feb 5;27(3):109122. doi: 10.1016/j.isci.2024.109122. eCollection 2024 Mar 15.

Authors

Jaime M Reyes^{1

2

3}, Ayala Tovy^{1

2}, Linda Zhang^{1

2

4

5}, Angelina S Bortoletto^{1

2

4

5}, Carina Rosas^{1

2}, Chun-Wei Chen^{1

2

3}, Sarah M Waldvogel^{1

2

6

5}, Anna G Guzman^{1

2}, Rogelio Aguilar^{1

7}, Sinjini Gupta^{1

2}, Ling Liu^{8

9}, Matthew T Buckley¹⁰, Kalyani R Patel¹¹, Andrea N Marcogliese¹¹, Yumei Li³, Choladda V Curry¹¹, Thomas Rando^{8

9}, Anne Brunet^{10

9}, Ronald J Parchem^{1

2}, Rachel E Rau^{1

7}, Margaret A Goodell^{1

2

3}

Affiliations

¹ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.
² Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴ Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
⁵ Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.
⁶ Cancer and Cell Biology Graduate Program, Baylor College of Medicine, Houston, TX, USA.
⁷ Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
⁸ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Paul F. Glenn Center for the Biology of Aging, Stanford University, Palo Alto, CA, USA.
¹⁰ Department of Genetics, Stanford University, Palo Alto, CA, USA.
¹¹ Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.

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.

Keywords: Epigenetics; Immunology; Physiology; Stem cells research; Transcriptomics.