Identification of In Vivo, Conserved, TAF15 RNA Binding Sites Reveals the Impact of TAF15 on the Neuronal Transcriptome

SummaryRNA binding proteins (RBPs) have emerged as major causative agents of amyotrophic lateral sclerosis (ALS). To investigate the function of TAF15, an RBP recently implicated in ALS, we explored its target RNA repertoire in normal human brain and mouse neurons. Coupling high-throughput sequencing of immunoprecipitated and crosslinked RNA with RNA sequencing and TAF15 knockdowns, we identified conserved TAF15 RNA targets and assessed the impact of TAF15 on the neuronal transcriptome. We describe a role of TAF15 in the regulation of splicing for a set of neuronal RNAs encoding proteins with essential roles in synaptic activities. We find that TAF15 is required for a critical alternative splicing event of the zeta-1 subunit of the glutamate N-methyl-D-aspartate receptor (Grin1) that controls the activity and trafficking of NR1. Our study uncovers neuronal RNA networks impacted by TAF15 and sets the stage for investigating the role of TAF15 in ALS pathogenesis.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Identification of in vivo TAF15 neuronal targets ► TAF15 regulates pre-mRNA splicing ► TAF15 targets transcripts coding for synaptic proteins ► TAF15 regulates alternative splicing of Grin1