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, Neville E. Sanjana

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number8362
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - 15 Dec 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

We thank the entire Sanjana and Mazzoni laboratories for support and advice and N. Dahmane for helpful feedback. We thank the NYU Biology Genomics Core for sequencing and flow cytometry resources. This work was supported by the NICHD (R01HD079682) to E.O.M. N.E.S. is supported by New York University and New York Genome Center startup funds, National Institutes of Health (NIH)/National Human Genome Research Institute (grant nos. R00HG008171, DP2HG010099, R01HG012790), NIH/National Cancer Institute (grant no. R01CA218668, R01CA279135), the NIH/National Institute of General Medical Sciences (R01GM138635), the NIH/National Institute of Allergy and Infectious Diseases (R01AI176601), the NIH/National Institute of Neurological Disorders and Stroke (R01NS124920), the MacMillan Center for the Study of the Noncoding Cancer Genome at the New York Genome Center, Defense Advanced Research Projects Agency (grant no. D18AP00053), the Simons Foundation for Autism Research (Genomics of ASD 896724), and the Brain and Behavior Foundation.

FundersFunder number
MacMillan Center for the Study
Simons Foundation for Autism ResearchASD 896724
National Institutes of Health
National Human Genome Research InstituteR00HG008171, DP2HG010099, R01HG012790
National Cancer InstituteR01CA218668, R01CA279135
National Institute of General Medical SciencesR01GM138635
National Institute of Allergy and Infectious DiseasesR01AI176601
National Institute of Neurological Disorders and StrokeR01NS124920
Defense Advanced Research Projects AgencyD18AP00053
Brain and Behavior Research Foundation
New York University
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentR01HD079682
New York Genome Center

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