AUTHOR=Mulligan Megan K., DuBose Candice , Yue Junming , Miles Michael F., Lu Lu , Hamre Kristin M.

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

JOURNAL=Frontiers in Genetics

VOLUME=4

YEAR=2013

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2013.00126

DOI=10.3389/fgene.2013.00126

ISSN=1664-8021

ABSTRACT=<p>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—<italic>Drosha, Pasha</italic>, and <italic>Dicer</italic>. 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 <italic>Dicer, Drosha, Pasha, Ars2 (Srrt</italic>), <italic>Eif2c1</italic> (<italic>Ago1</italic>), <italic>Eif2c2</italic> (<italic>Ago2</italic>), <italic>Zcchc11</italic>, and <italic>Snip1</italic>. 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 <italic>Dicer</italic> and <italic>Drosha</italic> in several brain regions and the response to many drugs of abuse, including ethanol, cocaine, and methamphetamine. Expression of <italic>Dicer, Drosha</italic>, and <italic>Pasha</italic> in most of the brain regions explored is strongly correlated with the expression of key members of the dopamine system. <italic>Drosha, Pasha</italic>, and <italic>Dicer</italic> 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.</p>