FOXO3 regulates Smad3 and Smad7 through SPON1 circular RNA to inhibit idiopathic pulmonary fibrosis
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ABSTRACT:
PROVIDER: PRJNA761975 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15828882_1.fastq.gz | Fastqsanger.gz | |||
| SRR15828882_2.fastq.gz | Fastqsanger.gz | |||
| SRR15828883_1.fastq.gz | Fastqsanger.gz | |||
| SRR15828883_2.fastq.gz | Fastqsanger.gz | |||
| SRR15828884_1.fastq.gz | Fastqsanger.gz |
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Project description:Forkhead box protein O3 (FOXO3) has good inhibition ability toward fibroblast activation and extracellular matrix, especially for the treatment of idiopathic pulmonary fibrosis. How FOXO3 regulates pulmonary fibrosis remains unclear. In this study, we reported that FOXO3 had binding sequences with F-spondin 1 (SPON1) promoter, which can activate its transcription and selectively promote the expression of SPON1 circRNA (circSPON1) but not mRNA expression. We further demonstrated that circSPON1 was involved in the extracellular matrix deposition of HFL1. In the cytoplasm, circSPON1 directly interacted with TGF-β-induced Smad3 and inhibited the activation of fibroblasts by inhibiting nuclear translocation. Moreover, circSPON1 bound to miR-942-5p and miR-520f-3p that interfered with Smad7 mRNA and promoted Smad7 expression. This study revealed the mechanism of FOXO3 in the occurrence and development of pulmonary fibrosis. Potential therapeutic targets and new insights into the diagnosis and treatment of idiopathic pulmonary fibrosis based on circRNA were also provided.
2021-09-10 | GSE183750 | GEO
Project description:Forkhead box protein O3 (FOXO3) has good inhibition ability toward fibroblast activation and extracellular matrix, especially for the treatment of idiopathic pulmonary fibrosis. How FOXO3 regulates pulmonary fibrosis remains unclear. In this study, we reported that FOXO3 had binding sequences with F-spondin 1 (SPON1) promoter, which can activate its transcription and selectively promote the expression of SPON1 circRNA (circSPON1) but not mRNA expression. We further demonstrated that circSPON1 was involved in the extracellular matrix deposition of HFL1. In the cytoplasm, circSPON1 directly interacted with TGF-β1-induced Smad3 and inhibited the activation of fibroblasts by inhibiting nuclear translocation. Moreover, circSPON1 bound to miR-942-5p and miR-520f-3p that interfered with Smad7 mRNA and promoted Smad7 expression. This study revealed the mechanism of FOXO3-regulated circSPON1 in the development of pulmonary fibrosis. Potential therapeutic targets and new insights into the diagnosis and treatment of idiopathic pulmonary fibrosis based on circRNA were also provided.
| S-EPMC10321294 | biostudies-literature
Project description:Background: Abnormal autophagy and TGFβ-SMAD3/7 signaling pathway plays an important role in intrauterine adhesions (IUA); however, the exact underlying mechanisms remain unclear. In this study, we aimed to detect whether SMAD7 effected IUA via regulating autophagy and TGFβ-SMAD3 signaling pathway. Methods: The expression of p-SMAD3 and SMAD7 were detected by Immunohistochemistry. Endometrial fibrosis was detected by masson staining. The expression of protein related to autophagy and fibrosis was detected by western blot. The autophagic flux was monitored via Tandem mRFP-GFP-LC3 fluorescence system. Chip assay was used for SMAD3 binding site analysis. SMAD7 knockout mice were used to investigate the regulation of SMAD7 on intrauterine adhesions and autophagy. Results: we observed that patients with IUA exhibited a lower expression of SMAD7. In endometrial stromal cells, the silencing of SMAD7 inhibited autophagic flux, whereas overexpressed SMAD7 promoted autophagic flux. We also found that SMAD7-mediated autophagic flux regulated stromal-myofibroblast transition. These phenotypes are regulated by the transforming growth factor (TGF)β-SMAD3 signaling pathway. We found that SMAD3 directly binds to the 3ʹ-untranslated region of transcription factor EB (TFEB) and inhibits its transcription. SMAD7 promoted autophagic flux by inhibiting SMAD3, thereby promoting the expression of TFEB. The endometria of SMAD7 knockout mice showed a fibrotic phenotype. Simultaneously, autophagic flux was inhibited. On administering the autophagy activator rapamycin, endometrial fibrosis of SMAD7 gene conditional knockout mice was partially restored. Conclusions: The loss of SMAD7 promotes endometrial fibrosis by inhibited autophagic flux via the TGFβ-SMAD3 pathway. Therefore, this study reveals a potential therapeutic target for IUA.
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Project description:Repair of the infarcted heart requires TGFβ-Smad3 signaling in cardiac myofibroblasts. However, TGF-β-driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7 may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of non-reperfused infarction, Smad3 activation triggered Smad7 synthesis in β-SMA+ infarct myofibroblasts, but not in β-SMA-/PDGFRα+ fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure-related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 actions on TGF-β cascades involved de-activation of Smad2/3 and non-Smad pathways, without any effects on TGF-β receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with Erbb2 in a TGF-independent manner and restrained Erbb1/Erbb2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-β-induced negative feedback mechanism that inhibits post-infarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-independent fibrogenic actions of Erbb2.
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Project description:Genome-wide binding profile of Smad3 and Smad7 in mouse Ch12 cell line (ChIP-Seq)
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Project description:Genome-wide binding profile of Smad3 and Smad7 in mouse Ch12 cell line (RNA-Seq)
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Project description:Long noncoding RNAs (lncRNAs) are involved in the regulation of skeletal muscle development. In the present study, differentially expressed lncRNAs were identified from RNA-seq data derived from myoblasts and myotubes. We conducted studies to elucidate the function and molecular mechanism of action of Linc-smad7 during skeletal muscle development. Our findings show that Linc-smad7 is upregulated during the early phase of myoblasts differentiation. In in vitro studies, we showed that overexpression of Linc-smad7 promoted the arrest of myoblasts in G1 phase, inhibited DNA replication, and induced myoblast differentiation. Our in vivo studies suggest that Linc-smad7 stimulates skeletal muscle regeneration in cardiotoxin-induced muscle injury. Mechanistically, Linc-smad7 overexpression increased smad7 and IGF2 protein levels. On the contrary, overexpression of miR-125b reduced smad7 and IGF2 protein levels. Results of RNA immunoprecipitation analysis and biotin-labeled miR-125b capture suggest that Linc-smad7 could act as a competing endogenous RNA (ceRNA) for miRNA-125b. Taken together, our findings suggest that the novel noncoding regulator Linc-smad7 regulates skeletal muscle development.
2017-11-01 | GSE106365 | GEO
Project description:Long-term management of inflammatory skin diseases is challenging because of side effects from repeated use of systemic treatments or topical corticosteroids. This study sought to identify novel mechanisms and developmental therapeutics for these diseases using genetic models and pharmacological approaches. We found mice overexpressing Smad7 in keratinocytes, but not mice overexpressing the N-terminal domain of Smad7 (N-Smad7), were resistant to imiquimod (IMQ)-induced Th1/17 and Th2 type inflammation. We generated a truncated Smad7 protein encompassing C-terminal Smad7 and PY motif fused with cell-penetrating Tat peptide (Tat-PYC-Smad7). Topically applied Tat-PYC-Smad7 to inflamed skin entered cells upon contact and attenuated IMQ-, 2,4-dinitrofluorobenzene-induced atopic dermatitis (AD) and tape-stripping inflammation (TS). RNAseq analyses of mouse skin exposed to these insults identified that in addition to inhibiting TGFβ/NFκB, Smad7 blunted IL22/STAT3 activation and associated pathogenesis, which is due to Smad7 transcriptionally upregulating IL22 antagonist IL22RA2. Mechanistically, Smad7 facilitated nuclear translocation and DNA binding of C/EBPβ to IL22RA2 promoter for IL22RA2 transactivation. Consistent to the above observations in mice, transcript levels of IL22RA2 were increased in human atopic dermatitis and psoriasis lesions with clinical remission. Our study identified the anti-inflammation functional domain of Smad7 and suggests mechanism and feasibility for developing Smad7-based biologics as a topical therapy for skin inflammatory disorders.
2023-06-12 | GSE231815 | GEO