Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells
Open accessAbstract
Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.
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Traditional methods such as GSEA overestimated the number of significant transcription factors, largely confounded by the large number of overlaps among putative target genes of different TFs.
“However, as we observed in our previous study53, traditional methods such as Gene Set Enrichment Analysis (GSEA) overestimated the number of significant transcription factors, largely confounded by the large number of overlaps among putative target genes of different TFs54.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [53]
In Results, under “miR-9 targets enriched for differentially expressed genes in SZ NPCs” (page unavailable), the paper warns that an enrichment analysis produced a very large list of significant miRNAs, likely confounded by overlapping predicted targets. It identifies the method as Partek Genomics Suite, not GSEA, and discusses miRNAs, not transcription factors; the cited passage therefore does not establish the claim about GSEA overestimating significant TFs. (LLM, conf=0.86)
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Self-citation
- Authors
- Topol, A., Zhu, S., Hartley, B. J., English, J., Hauberg, M. E., Tran, N., Rittenhouse, C. A., Simone, A., Ruderfer, D. M., Johnson, J., Readhead, B., Hadas, Y., Gochman, P. A., Wang, Y.-C., Shah, H., Cagney, G., Rapoport, J., Gage, F. H., Dudley, J. T., Sklar, P., Mattheisen, M., Cotter, D., Fang, G., & Brennand, K. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Royal College of Surgeons in Ireland (IE)
- Aarhus University (DK)
- Salk Institute for Biological Studies (US)
- National Institutes of Health (US)
- University College Dublin (IE)
- Corresponding author
- Fang, Gang
- Brennand, Kristen J.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 15
- Issue
- 5
- Pages
- 1024-1036
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4856588
- OpenAlex
- W2342348020
- Cited by
- 122
- References
- 41
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 14 · 2021: 16 · 2020: 16 · 2019: 11 · 2018: 22 · 2017: 18 · 2016: 7
- FWCI
- 8.06
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-09-05)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Brain and Behavior Research Foundation
- New York Stem Cell Foundation (R01 GM114472, R01 MH097276)
- Icahn School of Medicine at Mount Sinai
- Health Research Board
- National Institutes of Health (R01 MH101454, R01 MH106056)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- schizophrenia, miR-9, neural progenitor cells, neuronal migration, microRNA dysregulation, miRNA target genes, disease risk, patient-derived cells
- MeSH terms
- Cell Movement, Gene Expression Regulation, Humans, Models, Biological, Neurons, Schizophrenia, Transcription Factors, Case-Control Studies, Proteome, Gene Expression Profiling, MicroRNAs, Genetic Association Studies, Induced Pluripotent Stem Cells, Neural Stem Cells, Molecular Sequence Annotation
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