Diverse reprogramming codes for neuronal identity. Diverse reprogramming codes for neuronal identity

The transcriptional programs that establish neuronal identity evolved to produce a rich diversity of neuronal cell types that arise sequentially during development. Remarkably, transient expression of certain transcription factors (TFs) can also endow non-neural cells with neuronal properties. To decipher the relationship between reprogramming factors and transcriptional networks that produce neuronal identity and diversity, we screened ~600 TF pairs and identified 76 that produce induced neurons (iNs) from fibroblasts. By intersecting the transcriptomes of iNs with those of endogenous neurons, we define a “core” cell-autonomous neuronal signature. The iNs also exhibit diversity; each TF pair produces iNs with unique transcriptional patterns that can predict their pharmacological responses. By linking distinct TF input “codes” to defined transcriptional outputs, this study uncovers cell autonomous features of neuronal identity and expands the reprogramming toolbox to enable more facile engineering of induced neurons with desired patterns of gene expression and related functional properties. Overall design: RNA-Seq profiles for 35 TauEGFP-positive induced neuron populations, 1 embryonic fibroblast population, and 7 endogenous neural populations in biological duplicates. 2 endogenous neural populations were sequenced in biological triplicates. Single-cell RNA-Seq profiles for 4 TauEGFP-positive induced neuron populations and 1 Tau-EGFP-negative/positive mixed population.