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Essential transcription factors for induced neuron differentiation

Author

Listed:
  • Congyi Lu

    (New York Genome Center
    New York University)

  • Görkem Garipler

    (New York University)

  • Chao Dai

    (New York Genome Center
    New York University)

  • Timothy Roush

    (New York Genome Center
    New York University)

  • Jose Salome-Correa

    (New York Genome Center
    New York University)

  • Alex Martin

    (New York Genome Center
    New York University)

  • Noa Liscovitch-Brauer

    (New York Genome Center
    New York University)

  • Esteban O. Mazzoni

    (New York University
    NYU Grossman School of Medicine)

  • Neville E. Sanjana

    (New York Genome Center
    New York University)

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.

Suggested Citation

  • Congyi Lu & Görkem Garipler & Chao Dai & Timothy Roush & Jose Salome-Correa & Alex Martin & Noa Liscovitch-Brauer & Esteban O. Mazzoni & Neville E. Sanjana, 2023. "Essential transcription factors for induced neuron differentiation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43602-7
    DOI: 10.1038/s41467-023-43602-7
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