Cooperation between MEF2 and PPARγ in human intestinal β,β-carotene 15,15'-monooxygenase gene expression

We identified and functionally characterized the human BCMO1 promoter sequence and determined the transcriptional regulation of the BCMO1 gene in a BCMO1 expressing human intestinal cell line, TC-7. Several functional transcription factor-binding sites were identified in the human promoter that are absent in the mouse BCMO1 promoter. We demonstrate that the proximal promoter sequence, nt -190 to +35, confers basal transcriptional activity of the human BCMO1 gene. Site-directed mutagenesis of the myocyte enhancer factor 2 (MEF2) and peroxisome proliferator-activated receptor (PPAR) binding elements resulted in decreased basal promoter activity. Mutation of both promoter elements abrogated the expression of intestinal cell BCMO1. Electrophoretic mobility shift and supershift assays and transcription factor co-expression in TC-7 cells showed MEF2C and PPARγ bind to their respective DNA elements and synergistically transactivate BCMO1 expression.We demonstrate that human intestinal cell BCMO1 expression is dependent on the functional cooperation between PPARγ and MEF2 isoforms. The findings suggest that the interaction between MEF2 and PPAR factors may provide a molecular basis for interspecies differences in the transcriptional regulation of the BCMO1 gene.Vitamin A, an essential micronutrient, is required for embryonic development and pattern formation, postnatal growth, reproduction, epithelial maintenance, immunity and vision [1-5]. With the exception of the retina, where 11-cis-retinal acts as the chromophore for rhodopsin [6], biological activities of vitamin A are largely mediated by isomers of retinoic acid (RA). RAs bind members of the RA receptor (RAR) and retinoid X receptor (RXR) families of ligand-dependent transcription factors to regulate transcriptional rates of retinoid response genes. Vitamin A deficiency is associated with histological abnormalities in epithelial tissues [7], decreased host resistance to tumor cells and infectious organisms [8], and i