non-coding RNA and addiction

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Andre Pietrzykowski
Rutgers, The State University of New Jersey
Matthew Reilly
National Institute on Alcohol Abuse and Alcoholism (NIH)
Da-Yu Wu
National Institute on Drug Abuse (NIH)
Leonard Lipovich
School of Medicine, Wayne State University
Marissa A Ehringer
University of Colorado Boulder
Jonathan Pollock
National Institute on Drug Abuse (NIH)
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The miR-212/132 gene cluster is located on chromosome 17 in humans, 10 in rats, and 11 in mouse. Shown are mouse/human miR-212 and miR-132 genes, with locations of CRE elements through which CREB can stimulate miR-212 and miR-132 transcription.
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Review
13 June 2012
Global Approaches to the Role of miRNAs in Drug-Induced Changes in Gene Expression
Jodi E. Eipper-Mains
, 1 more and 
Richard E. Mains
miRNA biogenesis and gene silencing. (A) Transcription of a miRNA gene yields a capped, polyadenylated Pri-miRNA shown undergoing cleavage (red arrowheads) by Drosha (top, left). Transcription of a miRNA cluster yields a transcript encoding multiple miRNAs (top, right), each of which must be cleaved into a Pre-miRNA by Drosha. The mature or “guide” miRNA is shown in red, with the “star” or “passenger” strand shown in blue. Nuclear export of the Pre-miRNA requires Exportin-5. Cleavage of the Pre-miRNA by DICER (red arrowheads) generates a mature guide and star strand duplex; cleavage occurs in a protein complex that includes DICER, an Argonaute protein (AGO1-4), MOV10, TRBP, and additional proteins such as FMR1, DDX9, PUM2 (Schratt, 2009b; Czech and Hannon, 2011; De and MacRae, 2011). The star strand is lost from the final RISC and ultimately degraded, while the assembled RISC is available to bind to cognate RNAs and modulate protein expression. (B) Imperfect base complementarity. When the sequence of the miRNA guide strand does not perfectly match the target mRNA, translation of that mRNA is inhibited. Bound RISCs may contain any one of the four Argonaute proteins. The orange ball is the cap-binding complex; the large and small ribosomal subunits are shown in yellow. Perfect base complementarity. When the sequence of the miRNA guide strand matches the target mRNA perfectly, the target mRNA is sliced by AGO2.

Neurons modulate gene expression with subcellular precision through excitation-coupled local protein synthesis, a process that is regulated in part through the involvement of microRNAs (miRNAs), a class of small non-coding RNAs. The biosynthesis of miRNAs is reviewed, with special emphasis on miRNA families, the subcellular localization of specific miRNAs in neurons, and their potential roles in the response to drugs of abuse. For over a decade, DNA microarrays have dominated genome-wide gene expression studies, revealing widespread effects of drug exposure on neuronal gene expression. We review a number of recent studies that explore the emerging role of miRNAs in the biochemical and behavioral responses to cocaine. The more powerful next-generation sequencing technology offers certain advantages and is supplanting microarrays for the analysis of complex transcriptomes. Next-generation sequencing is unparalleled in its ability to identify and quantify low-abundance transcripts without prior sequence knowledge, facilitating the accurate detection and quantification of miRNAs expressed in total tissue and miRNAs localized to postsynaptic densities (PSDs). We previously identified cocaine-responsive miRNAs, synaptically enriched and depleted miRNA families, and confirmed cocaine-induced changes in protein expression for several bioinformatically predicted target genes. The miR-8 family was found to be highly enriched and cocaine-regulated at the PSD, where its members may modulate expression of cell adhesion molecules. An integrative approach that combines mRNA, miRNA, and protein expression profiling in combination with focused single gene studies and innovative behavioral paradigms should facilitate the development of more effective therapeutic approaches to treat addiction.

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21 citations
Hypothetical model for synaptic-related actions of miRNAs in brain of human alcoholics (e.g., in neurons). Ethanol can directly or indirectly affect multiple neurotransmitter receptors at the neuronal synapse and activate reward circuits conducive to multiple forms of neuronal plasticity, which in turn, convert the drug-induced signals into long-term alterations in behavior (e.g., alcohol dependency). The receptors affected on a particular synapse depend on the neuronal subtype and the specific subset of receptors expressed. For simplicity, several receptors such as GABAR, NMDAR, AChR, μOR, DRD, and β2AR, were diagramed as co-localized on the same synapse in the cartoon, but this is probably not the case in reality. miRNAs transported to and enriched in the synapses are locally processed by resident miRNA-ribonucleoprotein (miRNP) complexes (containing Dicer and FXR1P among other factors) and exert predominately inhibitory effects on mRNA targets also present at the specific synapses. Members of miRNA families, such as let-7, miR-1, miR-101, miR-140, and several others, downregulate the activity of neurotransmitter receptors by directly targeting respective mRNAs or by interfering with synaptic endocytosis (e.g., through targeting of dynamin and α-synuclein mRNAs). In addition, synaptic miRNAs implement negative feedback loops (through targeting of dicer and FXR1 mRNA, among other miRNA biogenesis-related factors) that auto-regulate their own availability. Such feedback loops ensure a balanced homeostatic control of a variety of synaptic functions. Concomitantly, cells implement miRNA-mediated epigenetics mechanisms, such as DNA methylation and histone methylation and/or acetylation, that ensure chromatin modification and global changes in gene expression that allow for long-term homeostatic changes and cellular adaptations under the particular environmental conditions. Expectedly, miRNAs that target epigenetic factors are also activated in order to control and/or fine-tune the ongoing remodeling of the cellular epigenome.
Review
03 April 2012

Advances in the fields of genomics and genetics in the last decade have identified a large number of genes that can potentially influence alcohol-drinking behavior in humans as well as animal models. Consequently, the task of identifying efficient molecular targets that could be used to develop effective therapeutics against the disease has become increasingly daunting. One of the reasons for this is the fact that each of the many alcohol-responsive genes only contributes a small effect to the overall mechanism and disease phenotype, as is characteristic of complex traits. Current research trends are hence shifting toward the analysis of gene networks rather than emphasizing individual genes. The discovery of microRNAs and their mechanisms of action on regulation of transcript level and protein translation have made evident the utility of these small non-coding RNA molecules that act as central coordinators of multiple cross-communicating cellular pathways. Cells exploit the fact that a single microRNA can target hundreds of mRNA transcripts and that a single mRNA transcript can be simultaneously targeted by distinct microRNAs, to ensure fine-tuned and/or redundant control over a large number of cellular functions. By the same token, we can use these properties of microRNAs to develop novel, targeted strategies to combat complex disorders. In this review, we will focus on recent discoveries of microRNA signatures in brain of human alcoholics supporting the hypothesis that changes in gene expression and regulation by microRNAs are responsible for long-term neuroadaptations occurring during development of alcoholism. We also discuss insights into the potential modulation of epigenetic regulators by a subset of microRNAs. Taken together, microRNA activity may be controlling many of the cellular mechanisms already known to be involved in the development of alcoholism, and suggests potential targets for the development of novel therapeutic interventions.

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60 citations
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18 citations