In silico analysis of the transcriptional regulatory logic of neuronal identity specification throughout the C. elegans nervous system

• DOI: 10.7554/elife.64906
• Publication Date: 2021-06-22T15:44:23Z
• Authors: Lori Glenwinkel; Seth R Taylor; Kasper Langebeck-...; Laura Pereira; Molly B Reilly; Manasa Basavaraju; Ibnul Rafi; Eviatar Yemini; Roger Pocock; Nenad Sestan; Marc Hammarlund; David M Miller; Oliver Hobert
• Keywords: Neurons; 0303 health sciences; QH301-705.5; Science; Q; R; Gene Expression Regulation, Developmental; cis-regulatory analysis; Cell Differentiation; Nervous System; 3. Good health; 03 medical and health sciences; Medicine; Animals; Computer Simulation; Biology (General); Caenorhabditis elegans; Caenorhabditis elegans Proteins; neuronal differentiation; transcription factor; Neuroscience; Transcription Factors

The generation of the enormous diversity of neuronal cell types in a differentiating nervous system entails the activation of neuron type-specific gene batteries. To examine the regulatory logic that controls the expression of neuron type-specific gene batteries, we interrogate single cell expression profiles of all 118 neuron classes of theCaenorhabditis elegansnervous system for the presence of DNA binding motifs of 136 neuronally expressedC. eleganstranscription factors. Using a phylogenetic footprinting pipeline, we identifycis-regulatory motif enrichments among neuron class-specific gene batteries and we identify cognate transcription factors for 117 of the 118 neuron classes. In addition to predicting novel regulators of neuronal identities, our nervous system-wide analysis at single cell resolution supports the hypothesis that many transcription factors directly co-regulate the cohort of effector genes that define a neuron type, thereby corroborating the concept of so-called terminal selectors of neuronal identity. Our analysis provides a blueprint for how individual components of an entire nervous system are genetically specified.