The Transcription Factor SCX is a Potential Serum Biomarker of Fibrotic Diseases

Ramírez-Aragón, Miguel; Hernández-Sánchez, Fernando; Rodríguez‐Reyna, Tatiana Sofía; Buendía-Roldán, Ivette; Güitrón-Castillo, Gael; Núñez‐Álvarez, Carlos A.; Hernández‐Ramírez, Diego F.; Suárez, Sergio Adán Benavides; Esquinca-González, Alexia; Torres-Machorro, Ana Lilia; Mendoza-Milla, Criselda

doi:10.3390/ijms21145012

Cited by 10 publications

(5 citation statements)

References 61 publications

(87 reference statements)

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“…However, because the dimer composition is very variable ( Table 3 , Table 4 and Table 5 ), it is proposed that future publications in the field should state the composition of the dimeric (or multimeric) bHLH TFs involved. As an example, in a study of the role of the bHLH TF SCX in tissue fibrosis, it was concluded that the relevant bHLH dimer is SCX/E47, as SCX by itself did not have a role in the experiments tested [ 274 ].…”

Section: Heterodimeric Interactions Among Bhlh Tfs Of Classes I Ii V and Vimentioning

confidence: 99%

Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix–Loop–Helix Transcription Factors

Torres-Machorro

2021

IJMS

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The basic helix–loop–helix transcription factor (bHLH TF) family is involved in tissue development, cell differentiation, and disease. These factors have transcriptionally positive, negative, and inactive functions by combining dimeric interactions among family members. The best known bHLH TFs are the E-protein homodimers and heterodimers with the tissue-specific TFs or ID proteins. These cooperative and dynamic interactions result in a complex transcriptional network that helps define the cell’s fate. Here, the reported dimeric interactions of 67 vertebrate bHLH TFs with other family members are summarized in tables, including specifications of the experimental techniques that defined the dimers. The compilation of these extensive data underscores homodimers of tissue-specific bHLH TFs as a central part of the bHLH regulatory network, with relevant positive and negative transcriptional regulatory roles. Furthermore, some sequence-specific TFs can also form transcriptionally inactive heterodimers with each other. The function, classification, and developmental role for all vertebrate bHLH TFs in four major classes are detailed.

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Section: Heterodimeric Interactions Among Bhlh Tfs Of Classes I Ii V and Vimentioning

confidence: 99%

Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix–Loop–Helix Transcription Factors

Torres-Machorro

2021

IJMS

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“…Several prognostic staging systems for IPF have been established by clinical and physiologic variables (2)(3)(4)(5). Biomarkers in peripheral blood are also evaluated as a tool for prognosis (6)(7)(8). A recent study also revealed the role of genetic variability in the survival of IPF (9).…”

Section: Introductionmentioning

confidence: 99%

Investigation of a Hypoxia-Immune-Related Microenvironment Gene Signature and Prediction Model for Idiopathic Pulmonary Fibrosis

Cai

et al. 2021

Front. Immunol.

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BackgroundThere is growing evidence found that the role of hypoxia and immune status in idiopathic pulmonary fibrosis (IPF). However, there are few studies about the role of hypoxia and immune status in the lung milieu in the prognosis of IPF. This study aimed to develop a hypoxia-immune-related prediction model for the prognosis of IPF.MethodsHypoxia and immune status were estimated with microarray data of a discovery cohort from the GEO database using UMAP and ESTIMATE algorithms respectively. The Cox regression model with the LASSO method was used for identifying prognostic genes and developing hypoxia-immune-related genes. Cibersort was used to evaluate the difference of 22 kinds of immune cell infiltration. Three independent validation cohorts from GEO database were used for external validation. Peripheral blood mononuclear cell (PBMC) and bronchoalveolar lavage fluid (BALF) were collected to be tested by Quantitative reverse transcriptase-PCR (qRT-PCR) and flow cytometry from 22 clinical samples, including 13 healthy controls, six patients with non-fibrotic pneumonia and three patients with pulmonary fibrosis.ResultsHypoxia and immune status were significantly associated with the prognosis of IPF patients. High hypoxia and high immune status were identified as risk factors for overall survival. CD8+ T cell, activated CD4+ memory T cell, NK cell, activated mast cell, M1 and M0 macrophages were identified as key immune cells in hypoxia-immune-related microenvironment. A prediction model for IPF prognosis was established based on the hypoxia-immune-related one protective and nine risk DEGs. In the independent validation cohorts, the prognostic prediction model performed the significant applicability in peripheral whole blood, peripheral blood mononuclear cell, and lung tissue of IPF patients. The preliminary clinical specimen validation suggested the reliability of most conclusions.ConclusionsThe hypoxia-immune-based prediction model for the prognosis of IPF provides a new idea for prognosis and treatment.

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“…Genes were ranked based on the significance of the differences in expression levels. Among the most-upregulated genes, we detected several typical genes involved in the fibrotic process such as SCX ( 33 ) and POSTN ( 34 ). Notably, the upregulation of IL-11 expression (2.83-fold, P=7.2×10 -4 ) defined the dominant transcriptional response of OFs to TGF-β1 ( Figure 4A ), which was further verified at the mRNA level by qRT-PCR and at protein levels by ELISA, both in TAO patients and in healthy controls in a time-dependent manner ( Figures 4B, C ).…”

Section: Resultsmentioning

confidence: 99%

IL-11 Is Elevated and Drives the Profibrotic Phenotype Transition of Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy

Lin

Huang

et al. 2022

Front. Endocrinol.

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Orbital fibrosis is a hallmark of tissue remodeling in thyroid-associated ophthalmopathy (TAO). Previous studies have shown that interleukin (IL)-11 plays a pivotal profibrotic role in various inflammatory and autoimmune diseases. However, the expression pattern of IL-11 in patients with TAO and whether IL-11 is mechanistically linked with pathological fibrosis remains unknown. In this study, we investigated IL-11 levels in the serum and orbital connective tissue of patients with TAO, and evaluated the correlation of these levels with the patient’s clinical activity score. We also evaluated the expression pattern of IL-11Rα in orbital connective tissue. Furthermore, we elucidated the regulatory factors, profibrotic function, and downstream signaling pathways for IL-11 in TAO using in vitro studies. IL-11 levels in serum and orbital connective tissues were increased in patients with TAO, as compared with healthy controls. In addition, both levels were positively correlated with disease activity. Single-cell RNA sequencing of orbital connective tissue indicated that IL-11Rα was dominantly expressed in orbital fibroblasts (OFs). RNA sequencing of paired unstimulated and transforming growth factor (TGF)-β1-stimulated samples demonstrated that upregulation of IL-11 expression defined the dominant transcriptional response. IL-11 signaling was also confirmed to be downstream of TGF-β1 and IL-1β. Therefore, we deduced that IL-11 protein is secreted in an autocrine loop in TAO. We also indicated that IL-11 mediated the profibrotic phenotype switch by inducing the expression of myofibroblast differentiation markers, including α-smooth muscle actin and collagen type I α1, which could be abrogated by an anti-IL-11 neutralizing antibody. Furthermore, we revealed that extracellular regulated protein kinase may be a crucial factor in the pro-fibrotic, translationally specific signaling activity of IL-11. These data demonstrate that IL-11 plays a crucial role in orbital fibroblast phenotype switching and may be a potential therapeutic target candidate for the treatment of TAO.

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The Transcription Factor SCX is a Potential Serum Biomarker of Fibrotic Diseases

Cited by 10 publications

References 61 publications

Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix–Loop–Helix Transcription Factors

Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix–Loop–Helix Transcription Factors

Investigation of a Hypoxia-Immune-Related Microenvironment Gene Signature and Prediction Model for Idiopathic Pulmonary Fibrosis

IL-11 Is Elevated and Drives the Profibrotic Phenotype Transition of Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy

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