Expression, covariation, and genetic regulation of miRNA Biogenesis genes in brain supports their role in addiction, psychiatric disorders, and disease

Megan K Mulligan,Michael F Miles,Lu Lu,Candice Dubose,Junming Yue,Kristin M Hamre

doi:10.3389/fgene.2013.00126

Megan K Mulligan, Michael F Miles + Show 4 more

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https://doi.org/10.3389/fgene.2013.00126

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Abstract

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.

Highlights

Small non-coding microRNAs are a recently discovered class of post-transcriptional regulatory molecules that control gene expression
Loading of miRNA into the RNA-induced silencing complex (RISC) is facilitated by TRBP and target matching between mRNAs and miRNAs occurs in the RISC, which is composed of Ago proteins and accessory proteins
EXPRESSION AND GENETIC REGULATION OF miRNA BIOGENESIS GENES IN MOUSE BRAIN Drosha, Pasha, and Dicer expression is measured from multiple probe sets that target different mRNA features

Summary

Introduction

Small non-coding microRNAs (miRNAs) are a recently discovered class of post-transcriptional regulatory molecules that control gene expression. Genes involved in the biogenesis of these regulatory RNAs include Dicer (Dicer1), Drosha, and Dgcr (Pasha). As part of the canonical pathway, Drosha and Pasha process pri-miRNA into pre-miRNA, which is transported into the cytoplasm via Exportin 5 (Bohnsack et al, 2004). Pre-miRNA is processed into miRNA by Dicer, Argonaute (Ago) proteins, accessory proteins, and TRBP. Several alternative and so-called non-canonical pathways for miRNA biogenesis exist, including a Dicer-dependent pathway which functions independently of Drosha and Pasha (Berezikov et al, 2007; Babiarz et al, 2008), and a Dicer-independent pathway that is dependent on the actions of Drosha and Ago (Cheloufi et al, 2010). Loss of function of any of these genes will have a severe impact of the miRNA landscape and the post-transcriptional regulation of mRNA (Babiarz et al, 2011)

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