Chromatin regulation by the nuclear receptor PPARbeta/delta

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The ligand-regulated nuclear receptor PPARβ/δ can both activate and repress transcription, but the regulation, mechanistic principles and biological consequences of these functions are only partly understood. By using a combination of chromatin immunoprecipitation (ChIP) sequencing and transcriptional profiling we have defined three distinct types of transcriptional responses of target genes to PPARβ/δ ligands or PPARβ/δ depletion. The molecular basis of these distinct target gene responses will be addressed in the proposed project. Our data also suggest that long-range interactions may be an important component of transcriptional regulation by PPARβ/δ. We will analyze the formation and functional implications of DNA looping by genome-wide ChIP-based technologies (ChIA-PET), gene-specific chromosome conformation assays and loss-of-function approaches. Furthermore, we have discovered new interaction partners of PPARβ/δ, including p18HAMLET, a subunit of SRCAP, which can insert histone variant H2A.Z into nucleosomes and thereby plays an essential role in myogenesis through regulation of the myogenin-encoding Myog gene, which we identified as a PPARβ/δ target. We will therefore analyze the influence of PPARβ/δ on genespecific and global organization of H2A.Z and correlate this with transcriptional profiling and the function of PPARβ/δ in myogenic differentiation. Finally, we have identified PIAS2 as an interaction partner of PPARβ/δ, and found that PPARβ/δ is polySUMOylated in a ligand-dependent way. We now plan to study the mechanism of ligand-mediated regulation of SUMOylation and to investigate its functional consequences.