Abstract

Role of CITED2 in Human Adipogenesis

Currently, there is an estimate of 160 million Americans who are obese and overweight1. Studying the molecular mechanisms that are involved in the development, maintenance, and regulation of adipocytes (fat cells) could provide insights on developing new tools to address such an issue. Human mesenchymal stem cells (hMSC) are adult stem cells capable of self-renewal and differentiation into multiple mature cell types. Upon receiving appropriate stimuli, hMSCs can differentiate into adipocytes, a process defined as adipogenesis. Here we use hMSCs to study the role of CITED2 gene, identified through a siRNAs high throughput screening, on adipogenesis. CITED2 encodes a Cbp/p300 Interacting Transactivator with Glu/Asp Rich Carboxy-Terminal Domain 2. Our study demonstrates that expression knockdown of CITED2 in hMSCs by siCITED2 promotes adipogenic differentiation of hMSCs, at least partly through promoting the expression of PPAR-gamma and CEBP-alpha, two transcription factors known as master regulators of adipogenesis. We further investigate how the effect of CITED2 might interact with that of SUV39H1, which is a histone lysine methyltransferase and also promotes adipogenesis upon its down-regulation, by comparing the effect of single knock-down (siCITED2 or siSUV39H1) vs. double knock-down (siCITED2 + siSUV39H1) on the expression of PPAR-gamma and CEBP-alpha. Our preliminary results demonstrate that when both genes are knocked down together, there is an additive effect in promoting adipogenesis as compared to that of single knock-down. Future studies will investigate how CITED2, a transcriptional co-regulator, and SUV39H1, an epigenetic regulator, might potentially physically interact to regulate the promoter activities of PPAR-gamma and CEBP-alpha genes.

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