CUX1 Manifests Species-Dependent Regulation in Controlling Adipocyte Differentiation [RNA-Seq]

Adipocyte differentiation, also known as adipogenesis, is a crucial process for maintaining the adipocyte pool and plays a key role in insulin sensitivity and systemic metabolism. Adipogenesis is governed by master transcription factors, such as C/EBPβ. However, there remains an unmet need to identify novel transcriptional factors within the C/EBPβ regulatory network in the differentiation of primary human adipose-derived precursor cells (hAPCs). Chromatin immunoprecipitation and selective isolation of chromatin-associated proteins (ChIP-SICAP) and CRISPR/cas9 knockout (KO) screening approach was applied in hAPCs. RNA-seq and ChIP-seq were also utilized for pathway and gene enrichment analyses. We also constructed a APCs-specific KO mouse model. Deletion of CUX1 in hAPCs impairs adipogenesis, whereas CUX1 overexpression (OE) increases human adipogenesis. RNA-seq and ChIP-seq analyses reveal that CUX1 promotes the expression of key adipogenic genes, including PPARG, a master regulator of adipocyte fate determination. Interestingly, Cux1 deletion enhances, while CUX1-OE suppresses adipogenesis in mouse APCs (mAPCs). ChIP-seq analysis of CUX1 in mAPCs further supports its contrasting role in mice. Additionally, in vivo tracing of mAPCs shows that Cux1 deletion promotes adipocyte differentiation. Collectively, these findings highlight that CUX1 exerts species-specific regulation of adipogenesis, acting as a differential regulator of fat development in humans and mice.