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SRSF6 is upregulated in asthmatic horses and involved in the MYH11 SMB expression.
Abstract: Smooth muscle has a central role in bronchospasm-induced airway obstruction in asthma. Alternative mRNA splicing of the smooth muscle myosin heavy chain (myh11) gene produces four different isoforms, one of which (SMB) is characterized by the inclusion of the exon5b, which doubles the smooth muscle cells contraction velocity. Deciphering the regulation of the expression levels of the SMB isoform would represent a major step for the understanding of the triggers and pathways leading to airway smooth muscle contraction in asthma. Our objective was therefore, to study the splicing regulation mechanisms of the exon5b in airway smooth muscle cells. Bioinformatics analysis was performed to identify the cis-regulatory elements present in the exon5b using HSF finder 3 tool. The expression of the corresponding serine/arginine rich protein (SR) genes thus identified was evaluated by quantitative RT-PCR (qPCR). SRSF1, SRSF6, and hnRNPA1 cis-acting elements were identified by in silico analysis of the exon5b sequence as splicing regulator candidates. QPCR analyses showed that SRSF1 and SRSF6 are upregulated in ASM cells from asthmatic horses in exacerbation (n = 5) compared to controls (n = 5). The inhibition of the identified splicing factors by small interfering RNA allowed identifying the regulation of the SMB isoform by SRSF6. Our results implicate for the first time the upregulation of SRSF6 and SRSF1 in the asthmatic ASM cells and indicate that SRSF6 induces the exon5b inclusion. This study provides an important first step for the understanding of the triggers and pathways leading to ASM hypercontraction and identifies a possible new target for asthma.
© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
Publication Date: 2018-10-24 PubMed ID: 30350466PubMed Central: PMC6198134DOI: 10.14814/phy2.13896Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research article delves into the role of a variant forms of myosin heavy chain protein, specifically SMB (Smooth Muscle Myosin isoform B), in causing airway muscle contraction in asthmatic horses which was found to be regulated by a protein known as SRSF6.
Objective of the Research
- The main objective of the study was to understand how the alternative splicing of the smooth muscle myosin heavy chain (myh11) gene, which produces four different isoforms including SMB, is regulated. The researchers were particularly interested in the mechanisms controlling the inclusion of the exon5b in airway smooth muscle cells as this increases the speed of muscle contraction.
Methods and Tools Used
- The researchers used bioinformatics analysis to identify the cis-regulatory elements present in exon5b. This was achieved using the HSF finder 3 tool.
- The expression levels of the corresponding SR genes identified were then tested using quantitative RT-PCR (qPCR).
- In silico analysis of the exon5b sequence was performed to recognize the cis-acting elements namely SRSF1, SRSF6, and hnRNPA1 as possible splicing regulator candidates.
- Finally, the role of these regulatory elements was confirmed by inhibiting them using small interfering RNA.
Major Findings
- The study discovered that SRSF1 and SRSF6 were upregulated in airway smooth muscle (ASM) cells from asthmatic horses.
- It was also found that SRSF6 regulates the generation of the SMB isoform i.e., it was responsible for the inclusion of exon5b in the myosin gene.
Conclusion
- The findings reveal the significant role that SRSF6 and SRSF1 play in asthmatic ASM cells.
- Moreover, the study indicates that SRSF6 is a key factor that triggers the inclusion of exon5b, thus leading to the generation of the SMB isoform which enhances muscle contraction in asthmatic horses.
- This research paves the way for better understanding the biological pathways leading to muscle hypercontraction in asthma, thereby suggesting a potential new target for therapeutic intervention.
Cite This Article
APA
Issouf M, Vargas A, Boivin R, Lavoie JP.
(2018).
SRSF6 is upregulated in asthmatic horses and involved in the MYH11 SMB expression.
Physiol Rep, 6(20), e13896.
https://doi.org/10.14814/phy2.13896 Publication
Researcher Affiliations
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Universitu00e9 de Montru00e9al, Saint-Hyacinthe, Quebec, Canada.
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Universitu00e9 de Montru00e9al, Saint-Hyacinthe, Quebec, Canada.
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Universitu00e9 de Montru00e9al, Saint-Hyacinthe, Quebec, Canada.
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Universitu00e9 de Montru00e9al, Saint-Hyacinthe, Quebec, Canada.
MeSH Terms
- Alternative Splicing
- Animals
- Asthma / genetics
- Asthma / metabolism
- Asthma / veterinary
- Cells, Cultured
- Horse Diseases / genetics
- Horse Diseases / metabolism
- Horses
- Lung / cytology
- Lung / metabolism
- Myocytes, Smooth Muscle / metabolism
- Myosin Heavy Chains / genetics
- Myosin Heavy Chains / metabolism
- Serine-Arginine Splicing Factors / genetics
- Serine-Arginine Splicing Factors / metabolism
- Up-Regulation
Grant Funding
- CIHR MOP-102751 / CIHR
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Citations
This article has been cited 4 times.- Jackson D, Walum J, Banerjee P, Lewis BW, Prakash YS, Sathish V, Xu Z, Britt RD Jr. Th1 cytokines synergize to change gene expression and promote corticosteroid insensitivity in pediatric airway smooth muscle.. Respir Res 2022 May 16;23(1):126.
- Van Den Broucke S, Vanoirbeek JAJ, Derua R, Hoet PHM, Ghosh M. Effect of Graphene and Graphene Oxide on Airway Barrier and Differential Phosphorylation of Proteins in Tight and Adherens Junction Pathways.. Nanomaterials (Basel) 2021 May 13;11(5).
- Nie MJ, Pan XT, Tao HY, Xu MJ, Liu SL, Sun W, Wu J, Zou X. Clinical and prognostic significance of MYH11 in lung cancer.. Oncol Lett 2020 Jun;19(6):3899-3906.
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