Transcriptional profiling identifies functional interactions of TGF β and PPAR β/δ signaling: synergistic induction of ANGPTL4 transcription.
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 angiopoietin-like 4 (ANGPTL4) gene as a model, we demonstrate that two enhancer regions cooperate to mediate the observed synergistic response. A TGFβ-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 TGFβ, it interacts with SMAD3, ETS1, RUNX2, and AP-1 in vivo, providing a possible mechanistic explanation for the observed synergism.
Kaddatz
Kerstin
K
Institute of Molecular Biology and Tumor Research, Philipps-University, Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany.
Adhikary
Till
T
Finkernagel
Florian
F
Meissner
Wolfgang
W
Müller-Brüsselbach
Sabine
S
Müller
Rolf
R
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C425931:GW 501516; D047494:PPAR delta; D048068:PPAR-beta; D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D013844:Thiazoles; D016212:Transforming Growth Factor beta