Genome-Wide Approaches to Dissect the Roles of RNA Binding Proteins in Translational Control: Implications for Neurological Diseases

Abstract

Translational control of messenger RNAs (mRNAs) is a key aspect of neurobiology, defects of which can lead to neurological diseases. In response to stimuli, local translation of mRNAs is activated at synapses to facilitate long-lasting forms of synaptic plasticity, the cellular basis for learning, and memory formation. Translation, as well as all other aspects of RNA metabolism, is controlled in part by RNA binding proteins (RBPs) that directly interact with mRNAs to form mRNA-protein complexes. Disruption of RBP function is becoming widely recognized as a major cause of neurological diseases. Thus understanding the mechanisms that govern the interplay between translation control and RBP regulation in both normal and diseased neurons will provide new opportunities for novel diagnostics and therapeutic intervention. As a means of studying translational control, genome-wide methods are emerging as powerful tools that have already begun to unveil mechanisms that are missed by single-gene studies. Here, we describe the roles of RBPs in translational control, review genome-wide approaches to examine translational control, and discuss how the application of these approaches may provide mechanistic insight into the pathogenic underpinnings of RBPs in neurological diseases.

An RNA-binding protein, Qki5, regulates embryonic neural stem cells through pre-mRNA processing in cell adhesion signaling

“…In such a complex context, it is difficult to precisely describe the biological and cellular roles of RNABPs (Irimia and Blencowe 2012;Kapeli and Yeo 2012). While classical biochemisty has provided mechanistic insights into RNA regulation, there is a gap between what can be learned from biochemical experiments and the intricacies of biological processes.…”

Drosophila Shep and C. elegans SUP-26 are RNA-binding proteins that play diverse roles in nervous system development

“…Loss of function of various RBPs often results in the development of neurological or neurodegenerative disease, suggesting that RNA regulation and consequently RBPs are critical to nervous system function (Lukong et al 2008;Zhou et al 2014;Kapeli and Yeo 2012;Holt and Schuman 2013;Hornberg and Holt 2013;Jung et al 2014). For example, loss of function of the RBP Fragile X Mental Retardation Protein (FMRP) leads to the most common form of mental retardation in humans, known as fragile X syndrome (Zarnescu et al 2005).…”

“…Increasing evidence suggests that RNAbinding proteins (RBPs) are important regulators of nervous system development that mediate posttranscriptional events such as RNA metabolism, splicing, localization, stability, and translation (Antonacci et al 2015;Olesnicky et al 2014;Rogulja-Ortmann et al 2014;Sharifnia and Jin 2014). Defects in RBP function have been linked to myriad neurological disorders including fragile X syndrome, spinal muscular atrophy, and amyotrophic lateral sclerosis (Lukong et al 2008;Zhou et al 2014;Kapeli and Yeo 2012;Holt and Schuman 2013;Jung et al 2014). Therefore, it is important to identify conserved RBPs and posttranscriptional mechanisms that regulate nervous system development across species.…”

The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation

“…The CLIP (cross-linking immunoprecipitation) approach with its many variations (including PAR-CLIP, iCLIP, HITS-CLIP) has been successfully used to map in vivo RNA-protein interactions for several RBPs in different experimental systems (for review, see Ascano et al 2012;Darnell 2012;Kapeli and Yeo 2012;König et al 2012). Here, we have used the iCLIP variant to identify endogenous RNA targets of Acinus in HeLa cells.…”