Mediator 25 (Med25) is a member of the mediator complex that relays signals from transcription factors to the RNA polymerase II machinery. Multiple transcription factors, particularly those involved in lipid metabolism, utilize the mediator complex, but how Med25 is involved in this context is unclear. We previously identified Med25 in a translatome screen of adult cardiomyocytes (CMs) in a novel cell type-specific model of LMNA cardiomyopathy. In this study, we show that Med25 upregulation is coincident with myocardial lipid accumulation. To ascertain the role of Med25 in lipid accumulation, we utilized iPSC-derived and neonatal CMs to recapitulate the in vivo phenotype by depleting lamins A and C (lamin A/C) in vitro. Although lamin A/C depletion elicits lipid accumulation, this effect appears to be mediated by divergent mechanisms dependent on the CM developmental state. To directly investigate Med25 in lipid accumulation, we induced adipogenesis in Med25-silenced 3T3-L1 preadipocytes and detected enhanced lipid accumulation. Assessment of pertinent mediators driving adipogenesis revealed that C/EBPα and PPARγ are super-induced by Med25 silencing. Our results indicate that Med25 limits adipogenic potential by suppressing the levels of master regulators that govern adipogenesis. Furthermore, we caution the use of early-developmental-stage cardiomyocytes to model adult-stage cells, particularly for dissecting metabolic perturbations emanating from LMNA mutations.
Saunders, Jasmine; Sikder, Kunal; Phillips, Elizabeth; Ishwar, Anurag; Mothy, David; Margulies, Kenneth B.; and Choi, Jason C., "Med25 Limits Master Regulators That Govern Adipogenesis" (2023). Department of Medicine Faculty Papers. Paper 409.
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This article is the author's final published version in International Journal of Molecular Sciences, Volume 24, Issue 7, 2023, Article number 6155.
The published version is available at https://doi.org/10.3390/ijms24076155. Copyright © 2023 by the authors. Licensee MDPI, Basel, Switzerland.