Loading...
Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ).
Adhikary, Till Kaddatz, Kerstin Finkernagel, Florian Schönbauer, Anne Meissner, Wolfgang Scharfe, Maren Jarek, Michael Blöcker, Helmut Müller-Brüsselbach, Sabine Müller, Rolf
Adhikary, Till
Kaddatz, Kerstin
Finkernagel, Florian
Schönbauer, Anne
Meissner, Wolfgang
Scharfe, Maren
Jarek, Michael
Blöcker, Helmut
Müller-Brüsselbach, Sabine
Müller, Rolf
Files
Loading...
Open Access publication
Adobe PDF, 808.09 KB
Other Titles
Abstract
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 PPARβ/δ-depleted human myofibroblasts to test this hypothesis and to identify global principles of PPARβ/δ-mediated gene regulation. Chromatin immunoprecipitation sequencing (ChIP-Seq) of PPARβ/δ, H3K4me3 and RNA polymerase II enrichment sites combined with transcriptional profiling enabled the definition of 112 bona fide PPARβ/δ target genes showing either of three distinct types of transcriptional response: (I) ligand-independent repression by PPARβ/δ; (II) ligand-induced activation and/or derepression by PPARβ/δ; and (III) ligand-independent activation by PPARβ/δ. These data identify PPRE-mediated repression as a major mechanism of transcriptional regulation by PPARβ/δ, 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 PPARβ/δ ligand-based drugs.
Citation
Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ). 2011, 6 (1):e16344 PLoS ONE
Publisher
Journal
PubMed ID
PubMed Central ID
Additional Links
Embedded video
Type
Article
Language
en
Description
Series/Report no.
ISSN
1932-6203