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Insight into genetic regulation of miRNA in mouse brain.

ABSTRACT: BACKGROUND:micro RNA (miRNA) are important regulators of gene expression and may influence phenotypes and disease traits. The connection between genetics and miRNA expression can be determined through expression quantitative loci (eQTL) analysis, which has been extensively used in a variety of tissues, and in both human and model organisms. miRNA play an important role in brain-related diseases, but eQTL studies of miRNA in brain tissue are limited. We aim to catalog miRNA eQTL in brain tissue using miRNA expression measured on a recombinant inbred mouse panel. Because samples were collected without any intervention or treatment (naïve), the panel allows characterization of genetic influences on miRNAs' expression levels. We used brain RNA expression levels of 881 miRNA and 1416 genomic locations to identify miRNA eQTL. To address multiple testing, we employed permutation p-values and subsequent zero permutation p-value correction. We also investigated the underlying biology of miRNA regulation using additional analyses, including hotspot analysis to search for regions controlling multiple miRNAs, and Bayesian network analysis to identify scenarios where a miRNA mediates the association between genotype and mRNA expression. We used addiction related phenotypes to illustrate the utility of our results. RESULTS:Thirty-eight miRNA eQTL were identified after appropriate multiple testing corrections. Ten of these miRNAs had target genes enriched for brain-related pathways and mapped to four miRNA eQTL hotspots. Bayesian network analysis revealed four biological networks relating genetic variation, miRNA expression and gene expression. CONCLUSIONS:Our extensive evaluation of miRNA eQTL provides valuable insight into the role of miRNA regulation in brain tissue. Our miRNA eQTL analysis and extended statistical exploration identifies miRNA candidates in brain for future study.

SUBMITTER: Kordas G

PROVIDER: S-EPMC6854704 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Insight into genetic regulation of miRNA in mouse brain.

Kordas Gordon G Rudra Pratyaydipta P Hendricks Audrey A Saba Laura L Kechris Katerina K

BMC genomics 20191113 1

<h4>Background</h4>micro RNA (miRNA) are important regulators of gene expression and may influence phenotypes and disease traits. The connection between genetics and miRNA expression can be determined through expression quantitative loci (eQTL) analysis, which has been extensively used in a variety of tissues, and in both human and model organisms. miRNA play an important role in brain-related diseases, but eQTL studies of miRNA in brain tissue are limited. We aim to catalog miRNA eQTL in brain ...[more]

PMID: 31722663

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Project description:The role of miRNA and miRNA biogenesis genes in the adult brain is just beginning to be explored. In this study we have performed a comprehensive analysis of the expression, genetic regulation, and co-expression of major components of the miRNA biogenesis pathway using human and mouse data sets and resources available on the GeneNetwork web site (genenetwork.org). We found a wide range of variation in expression in both species for key components of the pathway-Drosha, Pasha, and Dicer. Across species, tissues, and expression platforms all three genes are generally well-correlated. No single genetic locus exerts a strong and consistent influence on the expression of these key genes across murine brain regions. However, in mouse striatum, many members of the miRNA pathway are correlated-including Dicer, Drosha, Pasha, Ars2 (Srrt), Eif2c1 (Ago1), Eif2c2 (Ago2), Zcchc11, and Snip1. The expression of these genes may be partly influenced by a locus on Chromosome 9 (105.67-106.32 Mb). We explored ~1500 brain phenotypes available for the C57BL/6J × DBA/2J (BXD) genetic mouse population in order to identify miRNA biogenesis genes correlated with traits related to addiction and psychiatric disorders. We found a significant association between expression of Dicer and Drosha in several brain regions and the response to many drugs of abuse, including ethanol, cocaine, and methamphetamine. Expression of Dicer, Drosha, and Pasha in most of the brain regions explored is strongly correlated with the expression of key members of the dopamine system. Drosha, Pasha, and Dicer expression is also correlated with the expression of behavioral traits measuring depression and sensorimotor gating, impulsivity, and anxiety, respectively. Our study provides a global survey of the expression and regulation of key miRNA biogenesis genes in brain and provides preliminary support for the involvement of these genes and their product miRNAs in addiction and psychiatric disease processes.

Project description:BackgroundIt is known that some environmental chemicals affect the human endocrine system. The harmful effects of endocrine disrupting chemical (EDC) nonylphenol (NP) have been studied since the 1980s. It is known that NP adversely affects physiological functions by mimicking the natural hormone 17 beta-estradiol. In the present study, we analyzed the expression of miRNAs and their target genes in mouse Sertoli TM4 cells to better understand the regulatory roles of miRNAs on Sertoli cells after NP exposure.MethodsMouse TM4 Sertoli cells were treated with NP for 3 or 24 h, and global gene and miRNA expression were analyzed using Agilent mouse whole genome and mouse miRNA v13 arrays.ResultsWe identified genes that were > 2-fold differentially expressed in NP-treated cells and control cells (P < 0.05) and analyzed their functions through Gene Ontology analysis. We also identified miRNAs that were differentially expressed in NP-treated and control cells. Of the 186 miRNAs the expression of which differed between NP-treated and control cells, 59 and 147 miRNAs exhibited 1.3-fold increased or decreased expression at 3 and 24 h, respectively. Network analysis of deregulated miRNAs suggested that Ppara may regulate the expression of certain miRNAs, including miR-378, miR-125a-3p miR-20a, miR-203, and miR-101a, after exposure to NP. Additionally, comprehensive analysis of predicted target genes for miRNAs showed that the expression of genes with roles in cell proliferation, the cell cycle, and cell death were regulated by miRNA in NP-treated TM4 cells. Levels of expression of the miRNAs miR-135a* and miR-199a-5p were validated by qRT-PCR. Finally, miR-135a* target gene analysis suggests that the generation of reactive oxygen species (ROS) following exposure to NP exposure may be mediated by miR-135a* through regulation of the Wnt/beta-catenin signaling pathway.ConclusionsCollectively, these data help to determine NP's actions on mouse TM4 Sertoli cells and increase our understanding of the molecular mechanisms underlying the adverse effects of xenoestrogens on the reproductive system.

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Insight into genetic regulation of miRNA in mouse brain.

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Insight into genetic regulation of miRNA in mouse brain.

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