title: Role of Flightless-I (Drosophila) homolog in the transcription activation of type I collagen gene mediated by transforming growth factor beta.
abstract: Flightless-I (Drosophila) homolog (FLII) is a nuclear receptor coactivator that is known to interact with other transcriptional regulators such as the SWI/SNF complex, an ATP-dependent chromatin-remodeling complex, at the promoter or enhancer region of estrogen receptor (ER)-α target genes. However, little is known about the role of FLII during transcription initiation in the transforming growth factor beta (TGFβ)/SMAD-dependent signaling pathway. Here, we demonstrate that FLII functions as a coactivator in the expression of type I collagen gene induced by TGFβ in A549 cells. FLII activates the reporter gene driven by COL1A2 promoter in a dose-dependent manner. Co-expression of GRIP1, CARM1, or p300 did not show any synergistic activation of transcription. Furthermore, the level of COL1A2 expression correlated with the endogenous level of FLII mRNA level. Depletion of FLII resulted in a reduction of TGFβ-induced expression of COL1A2 gene. In contrast, over-expression of FLII caused an increase in the endogenous expression of COL1A2. We also showed that FLII is associated with Brahma-related gene 1 (BRG1) as well as SMAD in A549 cells. Notably, the recruitment of BRG1 to the COL1A2 promoter region was decreased in FLII-depleted A549 cells, suggesting that FLII is required for TGFβ-induced chromatin remodeling, which is carried out by the SWI/SNF complex. Furthermore, formaldehyde-assisted isolation of regulatory elements (FAIRE)-quantitative polymerase chain reaction (qPCR) experiments revealed that depletion of FLII caused a reduction in chromatin accessibility at the COL1A2 promoter. These results suggest that FLII plays a critical role in TGFβ/SMAD-mediated transcription of the COL1A2 gene through its role in recruiting the SWI/SNF complex to facilitate chromatin accessibility.
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea. Electronic address: kwjeong@gachon.ac.kr.
authors.forename: Kwang Won
authors.initials: KW
authors.lastname: Jeong
mesh_terms: D000072283:A549 Cells; D042002:Chromatin Assembly and Disassembly; D024042:Collagen Type I / Q000235:genetics*; D004265:DNA Helicases / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I; C098179:FLII protein, human; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: Chromatin remodeling; FLII; SWI/SNF complex; TGFβ