title: Olfactomedin 2, a novel regulator for transforming growth factor-β-induced smooth muscle differentiation of human embryonic stem cell-derived mesenchymal cells.
abstract: Transforming growth factor-β (TGF-β) plays an important role in smooth muscle (SM) differentiation, but the downstream target genes regulating the differentiation process remain largely unknown. In this study, we identified olfactomedin 2 (Olfm2) as a novel regulator mediating SM differentiation. Olfm2 was induced during TGF-β-induced SM differentiation of human embryonic stem cell-derived mesenchymal cells. Olfm2 knockdown suppressed TGF-β-induced expression of SM markers, including SM α-actin, SM22α, and SM myosin heavy chain, whereas Olfm2 overexpression promoted the SM marker expression. TGF-β induced Olfm2 nuclear accumulation, suggesting that Olfm2 may be involved in transcriptional activation of SM markers. Indeed, Olfm2 regulated SM marker expression and promoter activity in a serum response factor (SRF)/CArG box-dependent manner. Olfm2 physically interacted with SRF without affecting SRF-myocardin interaction. Olfm2-SRF interaction promoted the dissociation of SRF from HERP1, a transcriptional repressor. Olfm2 also inhibited HERP1 expression. Moreover, blockade of Olfm2 expression inhibited TGF-β-induced SRF binding to SM gene promoters in a chromatin setting, whereas overexpression of Olfm2 dose dependently enhanced SRF binding. These results demonstrate that Olfm2 mediates TGF-β-induced SM gene transcription by empowering SRF binding to CArG box in SM gene promoters.
authors.affiliation: Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602.
authors.forename: Ning
authors.initials: N
authors.lastname: Shi
authors.affiliation: Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602.
authors.forename: Xia
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602 sc229@uga.edu.
authors.forename: Shi-You
authors.initials: SY
authors.lastname: Chen
mesh_terms: D021581:Active Transport, Cell Nucleus; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D015870:Gene Expression; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000099251:Myocardin
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000099251:Myocardin; C405693:HEY2 protein, human; C000600297:OLFM2 protein, human; C581693:Olfml2a protein, human