Discovering therapeutic possibilities for polycystic ovary syndrome by targeting XIST and its associated ceRNA network through the analysis of transcriptome data
Abstract Long non-coding RNA (lncRNA) regulates many physiological processes by acting as competitive endogenous RNA (ceRNA). The dysregulation of lncRNA X-inactive specific transcript (XIST) has been shown in various human disorders. However, its role in the pathogenesis of polycystic ovary syndrom...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-56524-1 |
| _version_ | 1827316091635892224 |
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| author | Elahe Berenji Ali Valipour Motlagh Marziyeh Fathi Maryam Esmaeili Tayebeh Izadi Parsa Rezvanian Maryam Zanjirband Zahra Safaeinejad Mohammad Hossein Nasr-Esfahani |
| author_facet | Elahe Berenji Ali Valipour Motlagh Marziyeh Fathi Maryam Esmaeili Tayebeh Izadi Parsa Rezvanian Maryam Zanjirband Zahra Safaeinejad Mohammad Hossein Nasr-Esfahani |
| author_sort | Elahe Berenji |
| collection | DOAJ |
| description | Abstract Long non-coding RNA (lncRNA) regulates many physiological processes by acting as competitive endogenous RNA (ceRNA). The dysregulation of lncRNA X-inactive specific transcript (XIST) has been shown in various human disorders. However, its role in the pathogenesis of polycystic ovary syndrome (PCOS) is yet to be explored. This study aimed to explore the underlying mechanism of XIST in the pathogenesis of PCOS, specifically through dataset functional analysis. GEO PCOS datasets including RNA-seq, microarray, and miRNA-seq in granulosa cells (GCs) and blood, were examined and comprehensively analyzed. Enrichment analysis, ROC curve constructions, lncRNA-miRNA-mRNA interaction network analyses, and qRT-PCR validation were performed followed by a series of drug signature screenings. Our results revealed significant dysregulation in the expression of 1131 mRNAs, 30 miRNAs, and XIST in GCs of PCOS patients compared to healthy individuals. Of the120 XIST-correlated upregulated genes, 25 were enriched in inflammation-related pathways. Additionally, 5 miRNAs were identified as negative regulators of XIST-correlated genes. Accordingly, a ceRNA network containing XIST-miRNAs-mRNAs interactions was constructed. Furthermore, 6 genes, including AQP9, ETS2, PLAU, PLEK, SOCS3, and TNFRSF1B served as both GCs and blood-based biomarkers. By analyzing the number of interactions among XIST, miRNAs, and mRNAs, we pinpointed ETS2 as the pivotal gene within the ceRNA network. Our findings reveal a novel XIST- hsa-miR-146a-5p, hsa-miR-144-3p, and hsa-miR-1271-5p-ETS2 axis that comprehensively elucidates the XIST-associated mechanism underlying PCOS onset. qRT-PCR analysis further confirmed the, overexpression of both XIST and ETS2 . Furthermore, our results demonstrated that XIST and ETS2 were correlated with some assisted reproductive technologies outcomes. Finally, we identified two novel compounds including, methotrexate/folate and threonine using drug–gene interaction databases for PCOS management. These findings provide novel insights into the molecular etiology, diagnosis, and potential therapeutic interventions for PCOS. |
| first_indexed | 2024-04-24T23:07:37Z |
| format | Article |
| id | doaj.art-febddb4e29744443af78d2670531b15a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T23:07:37Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-febddb4e29744443af78d2670531b15a2024-03-17T12:24:55ZengNature PortfolioScientific Reports2045-23222024-03-0114112010.1038/s41598-024-56524-1Discovering therapeutic possibilities for polycystic ovary syndrome by targeting XIST and its associated ceRNA network through the analysis of transcriptome dataElahe Berenji0Ali Valipour Motlagh1Marziyeh Fathi2Maryam Esmaeili3Tayebeh Izadi4Parsa Rezvanian5Maryam Zanjirband6Zahra Safaeinejad7Mohammad Hossein Nasr-Esfahani8ACECR Institute of Higher Education (Isfahan Branch)Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECRACECR Institute of Higher Education (Isfahan Branch)Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECRDepartment of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECRDepartment of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECRDepartment of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECRDepartment of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECRDepartment of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECRAbstract Long non-coding RNA (lncRNA) regulates many physiological processes by acting as competitive endogenous RNA (ceRNA). The dysregulation of lncRNA X-inactive specific transcript (XIST) has been shown in various human disorders. However, its role in the pathogenesis of polycystic ovary syndrome (PCOS) is yet to be explored. This study aimed to explore the underlying mechanism of XIST in the pathogenesis of PCOS, specifically through dataset functional analysis. GEO PCOS datasets including RNA-seq, microarray, and miRNA-seq in granulosa cells (GCs) and blood, were examined and comprehensively analyzed. Enrichment analysis, ROC curve constructions, lncRNA-miRNA-mRNA interaction network analyses, and qRT-PCR validation were performed followed by a series of drug signature screenings. Our results revealed significant dysregulation in the expression of 1131 mRNAs, 30 miRNAs, and XIST in GCs of PCOS patients compared to healthy individuals. Of the120 XIST-correlated upregulated genes, 25 were enriched in inflammation-related pathways. Additionally, 5 miRNAs were identified as negative regulators of XIST-correlated genes. Accordingly, a ceRNA network containing XIST-miRNAs-mRNAs interactions was constructed. Furthermore, 6 genes, including AQP9, ETS2, PLAU, PLEK, SOCS3, and TNFRSF1B served as both GCs and blood-based biomarkers. By analyzing the number of interactions among XIST, miRNAs, and mRNAs, we pinpointed ETS2 as the pivotal gene within the ceRNA network. Our findings reveal a novel XIST- hsa-miR-146a-5p, hsa-miR-144-3p, and hsa-miR-1271-5p-ETS2 axis that comprehensively elucidates the XIST-associated mechanism underlying PCOS onset. qRT-PCR analysis further confirmed the, overexpression of both XIST and ETS2 . Furthermore, our results demonstrated that XIST and ETS2 were correlated with some assisted reproductive technologies outcomes. Finally, we identified two novel compounds including, methotrexate/folate and threonine using drug–gene interaction databases for PCOS management. These findings provide novel insights into the molecular etiology, diagnosis, and potential therapeutic interventions for PCOS.https://doi.org/10.1038/s41598-024-56524-1Polycystic ovary syndromeXISTceRNA networkBiomarkerDrug repositioning |
| spellingShingle | Elahe Berenji Ali Valipour Motlagh Marziyeh Fathi Maryam Esmaeili Tayebeh Izadi Parsa Rezvanian Maryam Zanjirband Zahra Safaeinejad Mohammad Hossein Nasr-Esfahani Discovering therapeutic possibilities for polycystic ovary syndrome by targeting XIST and its associated ceRNA network through the analysis of transcriptome data Scientific Reports Polycystic ovary syndrome XIST ceRNA network Biomarker Drug repositioning |
| title | Discovering therapeutic possibilities for polycystic ovary syndrome by targeting XIST and its associated ceRNA network through the analysis of transcriptome data |
| title_full | Discovering therapeutic possibilities for polycystic ovary syndrome by targeting XIST and its associated ceRNA network through the analysis of transcriptome data |
| title_fullStr | Discovering therapeutic possibilities for polycystic ovary syndrome by targeting XIST and its associated ceRNA network through the analysis of transcriptome data |
| title_full_unstemmed | Discovering therapeutic possibilities for polycystic ovary syndrome by targeting XIST and its associated ceRNA network through the analysis of transcriptome data |
| title_short | Discovering therapeutic possibilities for polycystic ovary syndrome by targeting XIST and its associated ceRNA network through the analysis of transcriptome data |
| title_sort | discovering therapeutic possibilities for polycystic ovary syndrome by targeting xist and its associated cerna network through the analysis of transcriptome data |
| topic | Polycystic ovary syndrome XIST ceRNA network Biomarker Drug repositioning |
| url | https://doi.org/10.1038/s41598-024-56524-1 |
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