Hepatic isomiR landscaping reveals new biological insights into metabolic dysfunction in steatotic liver disease
Post-transcriptionally modified microRNA (miRNA), called isomiRs, expand the repertoire of transcripts that can leveraged for therapeutic targets and biological insights. However, the expression of isomiRs has not been characterized in metabolic dysfunction-associated steatotic liver disease (MASLD)...
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15.04.2025
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| Abstract | Post-transcriptionally modified microRNA (miRNA), called isomiRs, expand the repertoire of transcripts that can leveraged for therapeutic targets and biological insights. However, the expression of isomiRs has not been characterized in metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, we assessed the isomiR expression profile in liver biopsies from 79 patients with MASLD and modeled their potential role in disease biology. MiRNAs represented 75% of the sequencing reads and over 65% of them were attributed to isomiRs, demonstrating their higher expression and diversity compared to canonically annotated miRNAs. Differential expression and machine-learning analyses were used to identify 173 isomiRs associated to MASLD severity and 58 isomiRs associated to fibrosis score. Candidate target mRNAs were identified for each isomiR based on sequence complementarity. Using matched mRNA sequencing data, and supported by data from an independent study, we proposed key dysregulated mRNA targets involved in a selection of 33 disease-associated pathways. Importantly, isomiRs offered novel and unique mRNA targets compared to the canonical miRNA, e.g. isomiR-122 targeting INSIG1 (insulin and cholesterol metabolism), and isomiR-21 targeting HMGCS2 and PPARA (PARR and TGF-beta signaling). Our work advances knowledge regarding the role of isomiRs in MASLD and lays a foundation for therapeutic targets identification.
Our results provide a comprehensive analysis of microRNA (isomiRs) in liver tissue. Machine learning identified isomiRs whose expression is associated with MASLD. Multi-omic analysis uncovered novel isomiR regulatory mechanisms involved in MASLD. |
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| AbstractList | Post-transcriptionally modified microRNA (miRNA), called isomiRs, expand the repertoire of transcripts that can leveraged for therapeutic targets and biological insights. However, the expression of isomiRs has not been characterized in metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, we assessed the isomiR expression profile in liver biopsies from 79 patients with MASLD and modeled their potential role in disease biology. MiRNAs represented 75% of the sequencing reads and over 65% of them were attributed to isomiRs, demonstrating their higher expression and diversity compared to canonically annotated miRNAs. Differential expression and machine-learning analyses were used to identify 173 isomiRs associated to MASLD severity and 58 isomiRs associated to fibrosis score. Candidate target mRNAs were identified for each isomiR based on sequence complementarity. Using matched mRNA sequencing data, and supported by data from an independent study, we proposed key dysregulated mRNA targets involved in a selection of 33 disease-associated pathways. Importantly, isomiRs offered novel and unique mRNA targets compared to the canonical miRNA, e.g. isomiR-122 targeting INSIG1 (insulin and cholesterol metabolism), and isomiR-21 targeting HMGCS2 and PPARA (PARR and TGF-beta signaling). Our work advances knowledge regarding the role of isomiRs in MASLD and lays a foundation for therapeutic targets identification.
Our results provide a comprehensive analysis of microRNA (isomiRs) in liver tissue. Machine learning identified isomiRs whose expression is associated with MASLD. Multi-omic analysis uncovered novel isomiR regulatory mechanisms involved in MASLD. |
| Author | Brion, Christian Hoang, Stephen A. Sakhamuri, Bhanu Ang, Jessie Wang, Guangliang Zhu, Zheng Siddiqui, Mohammad S. Salzman, David W. Mirshahi, Faridodin Asgharpour, Amon Long, Matthew R. Srour, Molly A. Hayes, David J. Foster, Neal C. Sanyal, Arun J. |
| Author_xml | – sequence: 1 givenname: Christian orcidid: 0000-0002-3548-1401 surname: Brion fullname: Brion, Christian organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 2 givenname: Stephen A. surname: Hoang fullname: Hoang, Stephen A. organization: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine; Richmond – sequence: 3 givenname: Guangliang surname: Wang fullname: Wang, Guangliang organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 4 givenname: Faridodin surname: Mirshahi fullname: Mirshahi, Faridodin organization: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine; Richmond – sequence: 5 givenname: Jessie surname: Ang fullname: Ang, Jessie organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 6 givenname: Matthew R. surname: Long fullname: Long, Matthew R. organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 7 givenname: Zheng surname: Zhu fullname: Zhu, Zheng organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 8 givenname: Bhanu surname: Sakhamuri fullname: Sakhamuri, Bhanu organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 9 givenname: Molly A. surname: Srour fullname: Srour, Molly A. organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 10 givenname: Mohammad S. surname: Siddiqui fullname: Siddiqui, Mohammad S. organization: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine; Richmond – sequence: 11 givenname: Amon surname: Asgharpour fullname: Asgharpour, Amon organization: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine; Richmond – sequence: 12 givenname: David J. surname: Hayes fullname: Hayes, David J. organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 13 givenname: Neal C. surname: Foster fullname: Foster, Neal C. organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 14 givenname: David W. surname: Salzman fullname: Salzman, David W. email: david.salzman@gatehousebio.com organization: Gatehouse Bio Inc.; 22 Strathmore Road – sequence: 15 givenname: Arun J. surname: Sanyal fullname: Sanyal, Arun J. email: david.salzman@gatehousebio.com organization: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine; Richmond |
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| Cites_doi | 10.1016/j.tibs.2022.06.005 |
| ContentType | Paper |
| Copyright | 2025, Posted by Cold Spring Harbor Laboratory |
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| DOI | 10.1101/2025.04.08.647685 |
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| Keywords | IsomiRs MicroRNA MASLD Liver Disease Fibrosis |
| Language | English |
| License | This pre-print is available under a Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0 |
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| Notes | Competing Interest Statement: CB, GW, JA, MRL, ZZ, BS, MAS, DJH, NCF, and DWS are employees and shareholders of Gatehouse Bio, and DWS and NCF serve on the Board of Directors. AJS has stock options in Tiziana, Inversago, Rivus, NorthSea, Durect. He has served as a consultant to Novo Nordisk, Eli Lilly, Boehringer Ingelhiem, Inventiva, Gilead, Takeda, LG Chem, Hanmi, Corcept, Surrozen, Poxel, 89 Bio, Boston Pharmaceuticals, Regeneron, Merck, Alnylam, Aligos, Akero, Myovant, Salix, Avant Sante, NorthSea Pharma, Madrigal, Path AI, Histoindex, Astra Zeneca, Abbvie, Zydus. His institution has received grants from Intercept, Novo Nordisk, Boehringer Ingelhiem, Eli Lilly, Merck, Takeda, Salix, Inventiva, Gilead, Akero, Hanmi, Histoindex, 89Bio. He receives royalties from Wolter Kluwers (UptoDate) and Elsevier. All other Authors declare that they have no competing interests. |
| ORCID | 0000-0002-3548-1401 |
| OpenAccessLink | https://www.biorxiv.org/content/10.1101/2025.04.08.647685 |
| PageCount | 32 |
| ParticipantIDs | biorxiv_primary_2025_04_08_647685 |
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| PublicationDate | 20250415 |
| PublicationDateYYYYMMDD | 2025-04-15 |
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| PublicationDecade | 2020 |
| PublicationTitle | bioRxiv |
| PublicationYear | 2025 |
| Publisher | Cold Spring Harbor Laboratory |
| Publisher_xml | – name: Cold Spring Harbor Laboratory |
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| Title | Hepatic isomiR landscaping reveals new biological insights into metabolic dysfunction in steatotic liver disease |
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