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Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex

Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small p...

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Autores principales: Santarelli, Danielle M., Carroll, Adam P., Cairns, Heath M., Tooney, Paul A., Cairns, Murray J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212302/
https://www.ncbi.nlm.nih.gov/pubmed/32006661
http://dx.doi.org/10.1016/j.gpb.2019.10.003
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author Santarelli, Danielle M.
Carroll, Adam P.
Cairns, Heath M.
Tooney, Paul A.
Cairns, Murray J.
author_facet Santarelli, Danielle M.
Carroll, Adam P.
Cairns, Heath M.
Tooney, Paul A.
Cairns, Murray J.
author_sort Santarelli, Danielle M.
collection PubMed
description Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA (miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex (BA 46) (n = 74 matched pairs of schizophrenia, schizoaffective, and control samples) was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92a, miR-495, and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that miRNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.
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spelling pubmed-72123022020-05-13 Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex Santarelli, Danielle M. Carroll, Adam P. Cairns, Heath M. Tooney, Paul A. Cairns, Murray J. Genomics Proteomics Bioinformatics Letter Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA (miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex (BA 46) (n = 74 matched pairs of schizophrenia, schizoaffective, and control samples) was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92a, miR-495, and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that miRNA dysregulation is an important factor in the complex pathophysiology of schizophrenia. Elsevier 2019-12 2020-02-14 /pmc/articles/PMC7212302/ /pubmed/32006661 http://dx.doi.org/10.1016/j.gpb.2019.10.003 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Letter
Santarelli, Danielle M.
Carroll, Adam P.
Cairns, Heath M.
Tooney, Paul A.
Cairns, Murray J.
Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex
title Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex
title_full Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex
title_fullStr Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex
title_full_unstemmed Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex
title_short Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex
title_sort schizophrenia-associated microrna–gene interactions in the dorsolateral prefrontal cortex
topic Letter
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212302/
https://www.ncbi.nlm.nih.gov/pubmed/32006661
http://dx.doi.org/10.1016/j.gpb.2019.10.003
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