Essential transcription factors for induced neuron differentiation

Congyi Lu, Görkem Garipler, Chao Dai, Timothy Roush, Jose Salome-Correa, Alex Martin, Noa Liscovitch-Brauer, Esteban O. Mazzoni () and Neville E. Sanjana ()
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Congyi Lu: New York Genome Center
Görkem Garipler: New York University
Chao Dai: New York Genome Center
Timothy Roush: New York Genome Center
Jose Salome-Correa: New York Genome Center
Alex Martin: New York Genome Center
Noa Liscovitch-Brauer: New York Genome Center
Esteban O. Mazzoni: New York University
Neville E. Sanjana: New York Genome Center

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Neurogenins are proneural transcription factors required to specify neuronal identity. Their overexpression in human pluripotent stem cells rapidly produces cortical-like neurons with spiking activity and, because of this, they have been widely adopted for human neuron disease models. However, we do not fully understand the key downstream regulatory effectors responsible for driving neural differentiation. Here, using inducible expression of NEUROG1 and NEUROG2, we identify transcription factors (TFs) required for directed neuronal differentiation by combining expression and chromatin accessibility analyses with a pooled in vitro CRISPR-Cas9 screen targeting all ~1900 TFs in the human genome. The loss of one of these essential TFs (ZBTB18) yields few MAP2-positive neurons. Differentiated ZBTB18-null cells have radically altered gene expression, leading to cytoskeletal defects and stunted neurites and spines. In addition to identifying key downstream TFs for neuronal differentiation, our work develops an integrative multi-omics and TFome-wide perturbation platform to rapidly characterize essential TFs for the differentiation of any human cell type.

Date: 2023
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DOI: 10.1038/s41467-023-43602-7

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