SHARP1/DEC2 inhibits adipogenic differentiation by regulating the activity of C/EBP

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Abstract
SHARP1, a basic helix–loop–helix transcription factor, is expressed in many cell types; however, the mechanisms by which it regulates cellular differentiation remain largely unknown. Here, we show that SHARP1 negatively regulates adipogenesis. Although expression of the early marker CCAAT/enhancer binding protein β (C/EBPβ) is not altered, its crucial downstream targets C/EBPα and peroxisome proliferator‐activated receptor γ (PPARγ) are downregulated by SHARP1. Protein interaction studies confirm that SHARP1 interacts with and inhibits the transcriptional activity of both C/EBPβ and C/EBPα, and enhances the association of C/EBPβ with histone deacetylase 1 (HDAC1). Consistently, in SHARP1‐expressing cells, HDAC1 and the histone methyltransferase G9a are retained at the C/EBP regulatory sites on the C/EBPα and PPARγ2 promoters during differentiation, resulting in inhibition of their expression. Interestingly, treatment with troglitazone results in displacement of HDAC1 and G9a, and rescues the differentiation defect of SHARP1‐overexpressing cells. Our data indicate that SHARP1 inhibits adipogenesis through the regulation of C/EBP activity, which is essential for PPARγ‐ligand‐dependent displacement of co‐repressors from adipogenic promoters.

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