Genomewide Analyses Define Different Modes of Transcriptional Regulation by Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ)

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with essential functions in lipid, glucose and energy homeostasis, cell differentiation, inflammation and metabolic disorders, and represent important drug targets. PPARs heterodimerize with retinoid X receptors (RXRs) and can form transcriptional activator or repressor complexes at specific DNA elements (PPREs). It is believed that the decision between repression and activation is generally governed by a ligand-mediated switch. We have performed genomewide analyses of agonist-treated and PPAR beta/delta-depleted human myofibroblasts to test this hypothesis and to identify global principles of PPAR beta/delta-mediated gene regulation. Chromatin immunoprecipitation sequencing (ChIP-Seq) of PPAR beta/delta, H3K4me3 and RNA polymerase II enrichment sites combined with transcriptional profiling enabled the definition of 112 bona fide PPAR beta/delta target genes showing either of three distinct types of transcriptional response: (I) ligand-independent repression by PPAR beta/delta; (II) ligand-induced activation and/or derepression by PPAR beta/delta; and (III) ligand-independent activation by PPAR beta/delta. These data identify PPRE-mediated repression as a major mechanism of transcriptional regulation by PPAR beta/delta, but, unexpectedly, also show that only a subset of repressed genes are activated by a ligand-mediated switch. Our results also suggest that the type of transcriptional response by a given target gene is connected to the structure of its associated PPRE(s) and the biological function of its encoded protein. These observations have important implications for understanding the regulatory PPAR network and PPAR beta/delta ligand-based drugs.