UNDERSTANDING THE FUNCTION OF UHRF1 IN ADIPOGENESIS

Abstract

The obesity epidemic is a global public health problem, and obese patients are at a higher risk of developing conditions like Type 2 Diabetes (T2D), cardiovascular complications, and cancer, among other comorbidities. Abnormal expansion of adipocytes, such as the increase in the size and/or number of adipocytes, has been closely associated with metabolic dysfunctions. Therefore, identifying molecular components that regulate adipogenesis is critical for developing new therapeutic strategies targeting obesity and related comorbidities. The E3 ubiquitin-ligase UHRF1 is a key epigenetic regulator coordinating DNA methylation and histone modifications. However, there is little known about its functional role in adipogenesis. In this study, we discovered that UHRF1 is a key regulatory factor adipogenesis and identified altered molecular and cellular pathways that are targeted by UHRF1. Using CRISPR-Cas9 based knockout strategies, we identified the whole transcriptomic changes compared to wild type. Bioinformatics and downstream analyses revealed that key adipogenesis regulators such as Peroxisome proliferator-activated receptor- (PPAR) and CCAAT-enhancer-binding proteins (C/EBPs) were suppressed, whereas TGF-β signaling and fibrosis inflammation markers were upregulated in UHRF1-null differentiating adipocytes compared to control cells. Furthermore, UHRF1 depleted cells showed upregulated expression and secretion profile of the glycoprotein GPNMB. Treating differentiating preadipocytes with recombinant GPNMB led to an increase in TGF-β proteins and secretion levels, which was accompanied by an increased secretion of fibrosis markers such as MMP13 and a reduction in adipogenesis differentiation potential, an outcome linked potentially to TGF-β induction. In conclusion, our data indicate that UHRF1 positively regulates 3T3-L1 adipogenesis by suppressing GPNMB and TGF-β signaling cascade, highlighting the potential relevance of UHRF1 and its targets to the clinical management of obesity and linked metabolic disorders.

Date of Award	2023
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences