Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ).

2.50
Hdl Handle:
http://hdl.handle.net/10033/181990
Title:
Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ).
Authors:
Adhikary, Till; Kaddatz, Kerstin; Finkernagel, Florian; Schönbauer, Anne; Meissner, Wolfgang; Scharfe, Maren; Jarek, Michael; Blöcker, Helmut; Müller-Brüsselbach, Sabine; Müller, Rolf
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.
Affiliation:
Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany.
Citation:
Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ). 2011, 6 (1):e16344 PLoS ONE
Journal:
PloS one
Issue Date:
2011
URI:
http://hdl.handle.net/10033/181990
DOI:
10.1371/journal.pone.0016344
PubMed ID:
21283829
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorAdhikary, Tillen
dc.contributor.authorKaddatz, Kerstinen
dc.contributor.authorFinkernagel, Florianen
dc.contributor.authorSchönbauer, Anneen
dc.contributor.authorMeissner, Wolfgangen
dc.contributor.authorScharfe, Marenen
dc.contributor.authorJarek, Michaelen
dc.contributor.authorBlöcker, Helmuten
dc.contributor.authorMüller-Brüsselbach, Sabineen
dc.contributor.authorMüller, Rolfen
dc.date.accessioned2011-10-28T10:55:24Z-
dc.date.available2011-10-28T10:55:24Z-
dc.date.issued2011-
dc.identifier.citationGenomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ). 2011, 6 (1):e16344 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid21283829-
dc.identifier.doi10.1371/journal.pone.0016344-
dc.identifier.urihttp://hdl.handle.net/10033/181990-
dc.description.abstractPeroxisome 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.en
dc.language.isoenen
dc.subject.meshCell Lineen
dc.subject.meshGene Expression Regulationen
dc.subject.meshGene Regulatory Networksen
dc.subject.meshGenome, Humanen
dc.subject.meshGenome-Wide Association Studyen
dc.subject.meshHumansen
dc.subject.meshPPAR deltaen
dc.subject.meshPPAR-betaen
dc.subject.meshPeroxisome Proliferator-Activated Receptorsen
dc.subject.meshResponse Elementsen
dc.subject.meshTranscription, Geneticen
dc.titleGenomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ).en
dc.typeArticleen
dc.contributor.departmentInstitute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany.en
dc.identifier.journalPloS oneen

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