Epigenetic regulation role of SUV420H in sexual dimorphism of adipose tissue and obesity

Abstract

Obesity is a worldwide health crisis linked to numerous harmful medical conditions. It arises from complex interactions between behavioral, environmental, and genetic factors. Interestingly, there is evidence of sexual dimorphism in the function of mitochondrial activity and metabolic flexibility of adipose tissue in obesity. Peroxisome proliferator-activated receptor-gamma (PPAR-γ), a critical factor in the formation of fat cells, glucose processing, and fat production, plays an essential role in the onset of obesity. Recently, it has been implicated in sex-based differences in adipose tissue gene expression and fat distribution. Epigenetic modifications mediate the effects of environmental factors by controlling the activity of genes related to metabolism. SUV420H1 and SUV420H2, histone methyltransferases that catalyze the addition of di- and trimethyl groups to lysine 20 of histone H4, suppress gene expression. Previous research has shown that SUV420H proteins respond to environmental signals by directly repressing PPAR-γ activity. In this study, we demonstrated that SUV420H1 and SUV420H2 are expressed differently between sexes in both human and mouse models. Interestingly, mice with a double knockout of Suv420h1 and Suv420h2 exhibit a sex-specific difference in their resistance to diet-induced obesity. Gene expression analysis of adipose tissue samples from obese humans reveals a significant inverse relationship between SUV420H and PPAR-γ expression in females, while no such correlation is observed in males. These findings highlight a potentially novel role for SUV420H proteins in modulating PPAR-γ activity, metabolic function, and the risk of obesity, with a clear sexual dimorphism in their effects.

Keywords

Epigenetics / Obesity / Sex / Adipose tissue / Gene expression

Acknowledgments

None.

Funding

Research in D.G.’s laboratory was supported by the Italian Ministry of Health (grant number RF-2018-12366631), the European Joint Program on Rare Diseases (grant number EJPRD20-191), the Italian Association for Cancer Research (grant number IG 2017-ID. 19919), and the National Institutes of Health—National Cancer Institute (grant number 1R21CA249378-01). S.P. was supported by the Italian Ministry of Health (grant number GR-2018- 12365314).

Conflict of interest

The authors declare that they have no competing interests.

Author contributions

Conceptualization: Davide Gabellini, Simona Pedrotti

Data curation: Simona Pedrotti

Formal analysis: Roberta Caccia

Funding acquisition: Simona Pedrotti, Davide Gabellini

Investigation: Simona Pedrotti

Methodology: Simona Pedrotti

Project administration: Simona Pedrotti, Davide Gabellini

Resources: Carmela Asteria, Lelio Morricone, Alessandro Giovanelli, Danilo Parolini, Alexis Elias Malavazos

Supervision: Davide Gabellini, Simona Pedrotti

Validation: Roberta Caccia, Arianna Segaloni, Giorgia Scichilone

Visualization: Davide Gabellini, Simona Pedrotti

Writing-original draft: Simona Pedrotti

Writing-review & editing: Davide Gabellini

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of all involved clinical centers (protocol code OBI-1, approved on February 13, 2020). All animal procedures were approved by the Institutional Animal Care and Use Committee of the IRCCS San Raffaele Scientific Institute and the Italian Ministry of Health and were communicated to local authorities according to Italian law.

Consent for publication

Informed consent was obtained from all subjects involved in the study.

Availability of data

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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