Tissue-selective, bidirectional regulation of PEX11α- and perilipin genes through a common peroxisome proliferator response element

Most cis-acting regulatory elements have generally been assumed to activate a single nearby gene. However, many genes are clustered together, raising the possibility that they are regulated through a common element. We show here that a single peroxisome proliferator response element (PPRE), located between the mouse PEX11alpha and perilipin genes, confers on both genes activation by peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma. A functional PPRE 8.4 kb downstream of the promoter of PEX11a, a PPARalpha target gene, was identified by a gene transfection study. This PPRE was positioned 1.9 kb upstream of the perilipin gene and also functioned with the perilipin promoter. In addition, this PPRE, when combined with the natural promoters of the PEX11alpha and perilipin genes, conferred subtype-selective activation by PPARalpha and PPARgamma2. The PPRE sequence specifically bound to the heterodimer of RXRalpha and PPARalpha or PPARgamma2, as assessed by electrophoretic gel mobility shift assays. Furthermore, tissue-selective binding of PPARalpha and PPARgamma to the PPRE was demonstrated in hepatocytes and adipocytes, respectively, by chromatin immuno-precipitation assay. Hence, the expression of these genes is induced through the same PPRE in the liver and adipose tissue, where the two PPAR subtypes are specifically expressed.