title: Accessible chromatin structure permits factors Sp1 and Sp3 to regulate human TGFBI gene expression.
abstract: Transforming growth factor beta 1-induced (TGFBI) protein is an extracellular matrix (ECM) protein that is associated with other ECM proteins and functions as a ligand for various types of integrins. In this study, we investigated how human TGFBI expression is regulated in lung and breast cancer cells. We observed that the TGFBI promoter in A549 and MBA-MD-231 cells, which constitutively express TGFBI, existed in an open chromatin conformation associated with transcriptionally permissive histone modifications. Moreover, we found that TGFBI expression required Sp1 transcription elements that can bind transcription factors Sp1 and Sp3 in vitro. Occupancy of the TGFBI promoter by Sp1 and Sp3 in vivo was only observed in TGFBI-expressing cells, indicating that open chromatin conformation might facilitate the binding of Sp1 and Sp3 to the TGFBI promoter region. TGFBI promoter activity was impaired when Sp1 elements were mutated, but was increased when Sp1 or Sp3 factors was overexpressed. Furthermore, Sp1 inhibition in vivo by mithramycin A, as well as knockdown of Sp1 and/or Sp3 expression by short interfering RNA, significantly reduced TGFBI mRNA and protein levels. Thus, our data demonstrated that the expression of TGFBI is well correlated with chromatin conformation at the TGFBI promoter, and that factors Sp1 and Sp3 are the primary determinants for the control of constitutive expression of TGFBI gene.
authors.affiliation: Department of Environmental Medical Biology, Institute of Tropical Medicine, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Jong-Joo
authors.initials: JJ
authors.lastname: Lee
authors.forename: Keunhee
authors.initials: K
authors.lastname: Park
authors.forename: Myeong Heon
authors.initials: MH
authors.lastname: Shin
authors.forename: Wook-Jin
authors.initials: WJ
authors.lastname: Yang
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Song
authors.forename: Joo-Hong
authors.initials: JH
authors.lastname: Park
authors.forename: Tai-Soon
authors.initials: TS
authors.lastname: Yong
authors.forename: Eung Kweon
authors.initials: EK
authors.lastname: Kim
authors.forename: Hyoung-Pyo
authors.initials: HP
authors.lastname: Kim
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D000099222:betaIG-H3 Protein
chemical_list: D002843:Chromatin; D016326:Extracellular Matrix Proteins; D006657:Histones; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C497121:SP3 protein, human