title: Activated Transcription Factor 3 in Association with Histone Deacetylase 6 Negatively Regulates MicroRNA 199a2 Transcription by Chromatin Remodeling and Reduces Endothelin-1 Expression.
abstract: Previous studies showed that high levels of placenta growth factor (PlGF) correlated with increased plasma levels of endothelin-1 (ET-1), a potent vasoconstrictor, in sickle cell disease (SCD). PlGF-mediated transcription of the ET-1 gene occurs by activation of hypoxia inducible factor 1α (HIF-1α) and posttranscriptionally by microRNA 199a2 (miR-199a2), which targets the 3' untranslated region (UTR) of HIF-1α mRNA. However, relatively less is known about how PlGF represses the expression of miR-199a2 located in the DNM3 opposite strand (DNM3os) transcription unit. Here, we show that PlGF induces the expression of activated transcription factor 3 (ATF3), which, in association with accessory proteins (c-Jun dimerization protein 2 [JDP2], ATF2, and histone deacetylase 6 [HDAC6]), as determined by proteomic analysis, binds to the DNM3os promoter. Furthermore, we show that association of HDAC6 with ATF3 at its binding site in this promoter was correlated with repression of miR-199a2 transcription, as shown by DNM3os transcription reporter and chromatin immunoprecipitation (ChIP) assays. Tubacin, an inhibitor of HDAC6, antagonized PlGF-mediated repression of DNM3os/pre-miR-199a2 transcription with a concomitant reduction in ET-1 levels in cultured endothelial cells. Analysis of lung tissues from Berkeley sickle (BK-SS) mice showed increased levels of ATF3 and increased expression of ET-1. Delivery of tubacin to BK-SS mice significantly attenuated plasma ET-1 and PlGF levels. Our studies demonstrated that ATF3 in conjunction with HDAC6 acts as a transcriptional repressor of the DNM3os/miR-199a2 locus.
authors: Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors: Chen
authors: C
authors: Li
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors: Yu
authors: Y
authors: Zhou
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Anastacia
authors: A
authors: Loberg
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors: Stanley M
authors: SM
authors: Tahara
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Punam
authors: P
authors: Malik
authors: Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA vkalra@usc.edu.
authors: Vijay K
authors: VK
authors: Kalra
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000755:Anemia, Sickle Cell / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D004195:Disease Models, Animal; D015536:Down-Regulation; D019332:Endothelin-1 / Q000235:genetics*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic; D040901:Proteomics / Q000379:methods; D014158:Transcription, Genetic
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D019332:Endothelin-1; D008565:Membrane Proteins; D035683:MicroRNAs; C098069:PIGF protein, human; C531408:mirn199 microRNA, human; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases