Transcriptional repression of peroxisome proliferator-activated receptor β/δ in murine keratinocytes by CCAAT/enhancer-binding proteins

The roles of peroxisome proliferator-activated receptors (PPARs) and CCAAT/enhancer-binding proteins (C/EBPs) in keratinocyte and sebocyte differentiation suggest that both families of transcription factors closely interact in the skin. Initial characterization of the mouse PPAR beta promoter revealed an AP-1 site that is crucial for the regulation of PPAR beta expression in response to inflammatory cytokines in the skin. We now present evidence for a novel regulatory mechanism of the expression of the PPAR beta gene by which two members of the C/EBP family of transcription factors inhibit its basal promoter activity in mouse keratinocytes. We first demonstrate that C/EBP alpha and C/EBP beta, but not C/EBP delta, inhibit the expression of PPAR beta through the recruitment of a transcriptional repressor complex containing HDAC-1 to a specific C/EBP binding site on the PPAR beta promoter. Consistent with this repression, the expression patterns of PPAR beta and C/EBPs are mutually exclusive in keratinocytes of the interfollicular epidermis and hair follicles in mouse developing skin. This work reveals the importance of the regulatory interplay between PPAR beta and C/EBP transcription factors in the control of proliferation and differentiation in this organ. Such insights are crucial for the understanding of the molecular control regulating the balance between proliferation and differentiation in many cell types including keratinocytes.