Dataset Information

Transcriptional profiling identifies functional interactions of TGF ? and PPAR ?/? signaling: synergistic induction of ANGPTL4 transcription.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) not only play a key role in regulating metabolic pathways but also modulate inflammatory processes, pointing to a functional interaction between PPAR and cytokine signaling pathways. In this study, we show by genome-wide transcriptional profiling that PPAR?/? and transforming growth factor-? (TGF?) pathways functionally interact in human myofibroblasts and that a subset of these genes is cooperatively activated by TGF? and PPAR?/?. Using the angiopoietin-like 4 (ANGPTL4) gene as a model, we demonstrate that two enhancer regions cooperate to mediate the observed synergistic response. A TGF?-responsive enhancer located ?8 kb upstream of the transcriptional start site is regulated by a mechanism involving SMAD3, ETS1, RUNX, and AP-1 transcription factors that interact with multiple contiguous binding sites. A second enhancer (PPAR-E) consisting of three juxtaposed PPAR response elements is located in the third intron ?3.5 kb downstream of the transcriptional start site. The PPAR-E is strongly activated by all three PPAR subtypes, with a novel type of PPAR response element motif playing a central role. Although the PPAR-E is not regulated by TGF?, it interacts with SMAD3, ETS1, RUNX2, and AP-1 in vivo, providing a possible mechanistic explanation for the observed synergism.

SUBMITTER: Kaddatz K

PROVIDER: S-EPMC2937979 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transcriptional profiling identifies functional interactions of TGF β and PPAR β/δ signaling: synergistic induction of ANGPTL4 transcription.

Kaddatz Kerstin K Adhikary Till T Finkernagel Florian F Meissner Wolfgang W Müller-Brüsselbach Sabine S Müller Rolf R

The Journal of biological chemistry 20100701 38

Peroxisome proliferator-activated receptors (PPARs) not only play a key role in regulating metabolic pathways but also modulate inflammatory processes, pointing to a functional interaction between PPAR and cytokine signaling pathways. In this study, we show by genome-wide transcriptional profiling that PPARβ/δ and transforming growth factor-β (TGFβ) pathways functionally interact in human myofibroblasts and that a subset of these genes is cooperatively activated by TGFβ and PPARβ/δ. Using the an ...[more]

PMID: 20595396

Similar Datasets

Project description:Perfluoroalkyl acids (PFAAs) are ubiquitous and persistent environmental contaminants. Compounds such as perfluoroocanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS) are readily found in the tissues of humans and wildlife. While PFOA and PFOS have been the subject of numerous studies since they were first described over a decade ago, less is known about the biological activity of PFHxS and PFNA. Most PFAAs are activators of peroxisome proliferator-activated receptor ? (PPAR?), although the biological effects of these compounds are likely mediated by other factors in addition to PPAR?. To evaluate the effects of PFHxS and PFNA, male wild-type and Ppar?-null mice were dosed by oral gavage with PFHxS (3 or 10mg/kg/day), PFNA (1 or 3mg/kg/day), or vehicle for 7days, and liver gene expression was evaluated by full-genome microarrays. Gene expression patterns were then compared to historical in-house data for PFOA and PFOS in addition to the experimental hypolipidemic agent, WY-14,643. While WY-14,643 altered most genes in a PPAR?-dependent manner, approximately 11-24% of regulated genes in PFAA-treated mice were independent of PPAR?. The possibility that PFAAs regulate gene expression through other molecular pathways was evaluated. Using data available through a microarray database, PFAA gene expression profiles were found to exhibit significant similarity to profiles from mouse tissues exposed to agonists of the constitutive activated receptor (CAR), estrogen receptor ? (ER?), and PPAR?. Human PPAR? and ER? were activated by all four PFAAs in trans-activation assays from the ToxCast screening program. Predictive gene expression biomarkers showed that PFAAs activate CAR in both genotypes and cause feminization of the liver transcriptome through suppression of signal transducer and activator of transcription 5B (STAT5B). These results indicate that, in addition to activating PPAR? as a primary target, PFAAs also have the potential to activate CAR, PPAR?, and ER? as well as suppress STAT5B.

Dataset Information

Transcriptional profiling identifies functional interactions of TGF ? and PPAR ?/? signaling: synergistic induction of ANGPTL4 transcription.

Publications

Transcriptional profiling identifies functional interactions of TGF β and PPAR β/δ signaling: synergistic induction of ANGPTL4 transcription.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets