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


Glenwinkel LLori , Taylor SRSeth R , Langebeck-Jensen KKasper , Pereira LLaura , Reilly MBMolly B , Basavaraju MManasa , Rafi IIbnul , Yemini EEviatar , Pocock RRoger , Sestan NNenad , Hammarlund MMarc , Miller DMDavid M , Hobert OOliver . eLife. 2021 06 24; 10().


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 the nervous system for the presence of DNA binding motifs of 136 neuronally expressed transcription factors. Using a phylogenetic footprinting pipeline, we identify 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.