Dataset Information

Molecular Mechanism of Mesenchyme Homeobox 1 in Transforming Growth Factor ?1-Induced P311 Gene Transcription in Fibrosis.

ABSTRACT: Organ fibrosis is characterized by excessive fibroblast, and extracellular matrix and the molecular basis are not fully elucidated. Recent studies have proven that P311, an 8-kDa conserved protein, could promote various organ fibrosis, such as skin, kidney, liver, and lung, partially through upregulating transforming growth factor ?1 (TGF-?1) translation. However, the upstream regulators and mechanism of P311 gene regulation remain unclear, although we previously found that cytokines, hypoxia, and TGF-?1 could upregulate P311 transcription. Here, we aimed to elucidate the molecular mechanism of TGF-?1-induced P311 transcriptional regulation, focusing on mesenchyme homeobox 1 (Meox1). In this article, we identified the core promoter of P311 through bioinformatics analysis and luciferase reporter assays. Moreover, we demonstrated that Meox1, induced by TGF-?1, could bind to the promoter of P311 and promote its transcriptional activity. Furthermore, the effect of Meox1 on P311 transcriptional expression contributed to altered migration and proliferation in human dermal fibroblast cells. In conclusion, we identified Meox1 as a novel transcription factor of P311 gene, providing a new clue of the pathogenesis in fibrosis.

SUBMITTER: Wei Z

PROVIDER: S-EPMC7199492 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecular Mechanism of Mesenchyme Homeobox 1 in Transforming Growth Factor β1-Induced <i>P311</i> Gene Transcription in Fibrosis.

Wei Zhiyuan Z Han Chao C Li Haisheng H He Weifeng W Zhou Junyi J Dong Hui H Wu Yuzhang Y Tian Yi Y Luo Gaoxing G

Frontiers in molecular biosciences 20200428

Organ fibrosis is characterized by excessive fibroblast, and extracellular matrix and the molecular basis are not fully elucidated. Recent studies have proven that P311, an 8-kDa conserved protein, could promote various organ fibrosis, such as skin, kidney, liver, and lung, partially through upregulating transforming growth factor β1 (TGF-β1) translation. However, the upstream regulators and mechanism of P311 gene regulation remain unclear, although we previously found that cytokines, hypoxia, a ...[more]

PMID: 32411720

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Project description:Myocardial fibrosis is often associated with cardiac hypertrophy; indeed, fibrosis is one of the most critical factors affecting prognosis. We aimed to identify the molecules involved in promoting fibrosis under hypertrophic stimuli. We previously established a rat model of cardiac hypertrophy by pulmonary artery banding, in which approximately half of the animals developed fibrosis in the right ventricle. Here, we first comprehensively analyzed mRNA expression in the right ventricle with or without fibrosis in pulmonary artery banding model rats by DNA microarray analysis (GSE141650 at NCBI GEO). The expression levels of 19 genes were up-regulated more than 1.5-fold in fibrotic hearts compared with non-fibrotic hearts. Among them, fibrosis growth factor (FGF) 23 showed one of the biggest increases in expression. Real-time PCR analysis also revealed that, among the FGF receptor (FGFR) family, FGFR1 was highly expressed in fibrotic hearts. We then found that FGF23 was expressed predominantly in cardiomyocytes, while FGFR1 was predominantly expressed in fibroblasts in the rat ventricle. Next, we added FGF23 and transforming growth factor (TGF)-?1 (10-50 ng/mL of each) to isolated fibroblasts from normal adult rat ventricles and cultured them for three days. While FGF23 itself did not directly affect the expression levels of any fibrosis-related mRNAs, FGF23 enhanced the effect of TGF-?1 on increasing the expression levels of ?-smooth muscle actin (?-SMA) mRNA. This increase in xx-SMA mRNA levels due to the combination of TGF-?1 and FGF23 was attenuated by the inhibition of FGFR1 or the knockdown of FGFR1 in fibroblasts. Thus, FGF23 synergistically promoted the activation of fibroblasts with TGF-?1, transforming fibroblasts into myofibroblasts via FGFR1. Thus, we identified FGF23 as a paracrine factor secreted from cardiomyocytes to promote cardiac fibrosis under conditions in which TGF-?1 is activated. FGF23 could be a possible target to prevent fibrosis following myocardial hypertrophy.

Project description:BackgroundEpithelial to mesenchymal transition, especially to myofibroblasts, plays an important role in wound healing, fibrosis, and carcinogenesis. Epidermal stem cells (EpSCs) are responsible for epidermal renewal and wound re-epithelialization. However, it remains unclear whether and how EpSCs transdifferentiate into myofibroblasts or myofibroblast-like cells (MFLCs). Here, we provide the first evidence showing that P311 induces EpSC to MFLC transdifferentiation (EpMyT) via TGFβ1/Smad signaling.MethodsWound healing and mesenchymal features were observed in the P311 KO and P311 WT mouse model of superficial second-degree burns. After the primary human or mouse EpSCs were forced to highly express P311 using an adenoviral vector, EpMyT was observed by immunofluorescence, real-time PCR, and western blot. The activity of TGFβ1 and Smad2/3 in EpSCs with different P311 levels was observed by western blot. The TβRI/II inhibitor LY2109761 and Smad3 siRNA were applied to block the EpMyT in P311-overexpressing EpSCs and exogenous TGFβ1 was to restore the EpMyT in P311 KO EpSCs. Furthermore, the mechanism of P311 regulating TGFβ1 was investigated by bisulfite sequencing PCR, luciferase activity assay, and real-time PCR.ResultsP311 KO mouse wounds showed delayed re-epithelialization and reduced mesenchymal features. The human or mouse EpSCs with overexpressed P311 exhibited fusiform morphological changes, upregulated expression of myofibroblast markers (α-SMA and vimentin), and downregulated expression of EpSC markers (β1-integrin and E-cadherin). P311-expressing EpSCs showed decreased TGFβ1 mRNA and increased TGFβ1 protein, TβRI/II mRNA, and activated Smad2/3. Moreover, LY2109761 and Smad3 siRNA reversed P311-induced EpMyT. Under the stimulation of exogenous TGFβ1, the phosphorylation of Smad2 and Smad3 in P311 KO EpSCs was significantly lower than that in P311 WT EpSCs and the EpMyT in P311 KO EpSCs was restored. Furthermore, P311 enhanced the methylation of TGFβ1 promoter and increased activities of TGFβ1 5'/3' untranslated regions (UTRs) to stimulate TGFβ1 expression. P311+α-SMA+ cells and P311+vimentin+ cells were observed in the epidermis of human burn wounds. Also, P311 was upregulated by IL-1β, IL-6, TNFα, and hypoxia.ConclusionsP311 is a novel TGFβ1/Smad signaling-mediated regulator of transdifferentiation in EpSCs during cutaneous wound healing. Furthermore, P311 might stimulate TGFβ1 expression by promoting TGFβ1 promoter methylation and by activating the TGFβ1 5'/3' UTR.

Dataset Information

Molecular Mechanism of Mesenchyme Homeobox 1 in Transforming Growth Factor ?1-Induced P311 Gene Transcription in Fibrosis.

Publications

Molecular Mechanism of Mesenchyme Homeobox 1 in Transforming Growth Factor β1-Induced <i>P311</i> Gene Transcription in Fibrosis.

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