Diverse reprogramming codes for neuronal identity

The transcriptional programs that establish neuronal identity evolved to produce the rich diversity of neuronal cell types that arise sequentially during development. Remarkably, transient expression of certain transcription factors can also endow non-neural cells with neuronal properties. The relat...

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Bibliographic Details
Published in:Nature (London) Vol. 557; no. 7705; pp. 375 - 380
Main Authors: Tsunemoto, Rachel, Lee, Sohyon, Szűcs, Attila, Chubukov, Pavel, Sokolova, Irina, Blanchard, Joel W., Eade, Kevin T., Bruggemann, Jacob, Wu, Chunlei, Torkamani, Ali, Sanna, Pietro Paolo, Baldwin, Kristin K.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.05.2018
Nature Publishing Group
Subjects:
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Animals
Bioinformatics
Cell division
Cellular Reprogramming - genetics
Cloning
DNA binding proteins
Fibroblasts
Fibroblasts - cytology
Fibroblasts - metabolism
Gene expression
Gene Expression Profiling
Gene Regulatory Networks
Genes
Genomes
Humanities and Social Sciences
Humans
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Mice
multidisciplinary
Neural circuitry
Neurons
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Neurophysiology
Pharmacology
Physiological aspects
Science
Science (multidisciplinary)
Sequence Analysis, RNA
Single-Cell Analysis
Transcription (Genetics)
Transcription factors
Transcription Factors - metabolism
Transcriptome - genetics
ISSN:0028-0836, 1476-4687, 1476-4687
Online Access:Get full text
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Summary:The transcriptional programs that establish neuronal identity evolved to produce the rich diversity of neuronal cell types that arise sequentially during development. Remarkably, transient expression of certain transcription factors can also endow non-neural cells with neuronal properties. The relationship between reprogramming factors and the transcriptional networks that produce neuronal identity and diversity remains largely unknown. Here, from a screen of 598 pairs of transcription factors, we identify 76 pairs of transcription factors that induce mouse fibroblasts to differentiate into cells with neuronal features. By comparing the transcriptomes of these induced neuronal cells (iN cells) with those of endogenous neurons, we define a ‘core’ cell-autonomous neuronal signature. The iN cells also exhibit diversity; each transcription factor pair produces iN cells with unique transcriptional patterns that can predict their pharmacological responses. By linking distinct transcription factor input ‘codes’ to defined transcriptional outputs, this study delineates cell-autonomous features of neuronal identity and diversity and expands the reprogramming toolbox to facilitate engineering of induced neurons with desired patterns of gene expression and related functional properties. A screen in which combinatorial pairs of transcription factors are exogenously expressed in fibroblasts identifies different combinations that reprogram these cells into induced neuronal cells with diverse functional properties.
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J.B. performed HOMER motif enrichment analysis. C.W. made data available through BioGPS.org. R.T. and S.L. performed all remaining experiments.
Author contributions K.K.B., R.T and S.L. designed and conceived the experiments, wrote and revised the manuscript and all of the authors edited the final drafts. K.TE., J.W.B. and R.T performed and analysed the screen experiments. A.S., I.S. and PPS. performed electrophysiology. R.T, S.L. and PC. prepared cDNA libraries. R.T, S.L., PC. and A.T. performed RNA-seq analysis.
ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-018-0103-5