Tissue-Selective, Bidirectional Regulation of PEX11α and Perilipin Genes through a Common Peroxisome Proliferator Response Element

Abstract

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 PEX11α and perilipin genes, confers on both genes activation by peroxisome proliferator-activated receptor alpha (PPARα) and PPARγ. A functional PPRE 8.4 kb downstream of the promoter of PEX11α, a PPARα 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 PEX11α and perilipin genes, conferred subtype-selective activation by PPARα and PPARγ2. The PPRE sequence specifically bound to the heterodimer of RXRα and PPARα or PPARγ2, as assessed by electrophoretic gel mobility shift assays. Furthermore, tissue-selective binding of PPARα and PPARγ to the PPRE was demonstrated in hepatocytes and adipocytes, respectively, by chromatin immunoprecipitation 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.

We thank B. M. Spiegelman, G. MacGregor, P. A. Grimaldi, the late K. Umesono, and R. M. Evans for the plasmids. We also thank Y. Emi for a mouse genomic library.

This work was supported in part by the 21st Century COE Program and a Grand-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.