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Published on: June 27, 2017
MicroRNA isomiRs reveal novel pathways linked to disease activity and fibrosis in MASLD
Christian Brion1, Stephen A Hoang2, Guangliang Wang1
1Gatehouse Bio Inc., Natick, MA, USA.
Background/Aims:
MicroRNA (miRNA) isoforms (isomiRs) broaden the regulatory landscape of canonical miRNAs, but their role in metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown. We aimed to characterize the hepatic isomiR landscape in MASLD and define their association with disease activity and fibrosis.
Methods:
Small RNA (sRNA) sequencing was performed on liver biopsies from 79 patients across the histological spectrum of MASLD. IsomiRs were annotated and quantified. Their association to disease activity and fibrosis score was assessed by differential expression, ordinal regression, and machine learning. Parallel mRNA sequencing and pathway enrichment were used to map isomiR-mRNA interactions and regulatory networks, which were validated against an independent dataset.
Results:
MiRNAs accounted for 75% of sRNAs in liver tissue, of which 67% were isomiRs. Across MASLD severity, 173 isomiRs correlated with disease activity and 58 with fibrosis stage. Key findings included a miR-122 isomiR uniquely targeting INSIG1 (cholesterol metabolism) and a miR-21 isomiR targeting PPARA and HMGCS2 (lipid and fibrosis pathways). Integration with mRNA data revealed 33 dysregulated pathways, including PPAR signaling, insulin resistance, and TGF-β response. Several novel isomiRs from miR-26b, let-7c, and miR-32 families were also linked to lipid metabolism and fibrosis progression.
Conclusions:
IsomiRs represent the majority of hepatic miRNAs and uncover novel regulatory networks masked by canonical miRNA analysis. These findings provide new insights into the molecular heterogeneity of MASLD, highlight candidate pathways driving disease progression, and identify potential biomarkers and therapeutic targets for precision hepatology.
Insights
MicroRNA isoforms (isomiRs) are abundant in the liver and reveal new molecular pathways in metabolic dysfunction-associated steatotic liver disease (MASLD). These findings offer potential biomarkers and therapeutic targets for MASLD.
Area of Science:
- Genomics
- Molecular Biology
- Hepatology
Background:
- MicroRNA isoforms (isomiRs) are largely uncharacterized in metabolic dysfunction-associated steatotic liver disease (MASLD).
- Understanding isomiRs is crucial for elucidating the complex regulatory networks in liver disease.
Purpose of the Study:
- To characterize the hepatic isomiR landscape in MASLD.
- To define the association of isomiRs with MASLD activity and fibrosis.
- To identify novel regulatory networks and potential therapeutic targets in MASLD.
Main Methods:
- Small RNA sequencing of 79 liver biopsies from MASLD patients.
- Annotation and quantification of isomiRs.
- Differential expression analysis, ordinal regression, and machine learning to assess associations with disease severity.
- Parallel mRNA sequencing and pathway enrichment analysis to map interactions.
Main Results:
- IsomiRs constitute 67% of hepatic microRNAs.
- 173 isomiRs correlated with disease activity and 58 with fibrosis stage in MASLD.
- Identified novel isomiR targets in cholesterol and lipid metabolism, including miR-122 targeting INSIG1 and miR-21 targeting PPARA and HMGCS2.
- Revealed dysregulated pathways such as PPAR signaling and insulin resistance.
Conclusions:
- IsomiRs are the predominant form of hepatic microRNAs, offering insights beyond canonical miRNA analysis.
- IsomiRs uncover novel regulatory networks critical to MASLD pathogenesis.
- Identified potential diagnostic biomarkers and therapeutic targets for precision hepatology in MASLD.
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