TY - JOUR TI - Splicing in a single neuron is coordinately controlled by RNA binding proteins and transcription factors AU - Thompson, Morgan AU - Bixby, Ryan AU - Dalton, Robert AU - Vandenburg, Alexa AU - Calarco, John A AU - Norris, Adam D A2 - Hobert, Oliver A2 - Manley, James L A2 - Kuroyanagi, Hidehito VL - 8 PY - 2019 DA - 2019/07/19 SP - e46726 C1 - eLife 2019;8:e46726 DO - 10.7554/eLife.46726 UR - https://doi.org/10.7554/eLife.46726 AB - Single-cell transcriptomes are established by transcription factors (TFs), which determine a cell's gene-expression complement. Post-transcriptional regulation of single-cell transcriptomes, and the RNA binding proteins (RBPs) responsible, are more technically challenging to determine, and combinatorial TF-RBP coordination of single-cell transcriptomes remains unexplored. We used fluorescent reporters to visualize alternative splicing in single Caenorhabditis elegans neurons, identifying complex splicing patterns in the neuronal kinase sad-1. Most neurons express both isoforms, but the ALM mechanosensory neuron expresses only the exon-included isoform, while its developmental sister cell the BDU neuron expresses only the exon-skipped isoform. A cascade of three cell-specific TFs and two RBPs are combinatorially required for sad-1 exon inclusion. Mechanistically, TFs combinatorially ensure expression of RBPs, which interact with sad-1 pre-mRNA. Thus a combinatorial TF-RBP code controls single-neuron sad-1 splicing. Additionally, we find ‘phenotypic convergence,’ previously observed for TFs, also applies to RBPs: different RBP combinations generate similar splicing outcomes in different neurons. KW - RNA KW - splicing KW - single neuron JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -