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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

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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

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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.

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