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An integrative CRISPR screen reveals the AP-1 transcription factor complex mediates activation of the human neural crest cell gene regulatory program

ABSTRACT: The complex interplay between signaling systems, transcription factors, and cis-regulatory elements required for development are encoded within gene regulatory networks (GRN). Although GRNs have greatly expanded our understanding of cell fate decisions during embryogenesis, they are typically assembled via a candidate-based approach, which fails to consider the tissue specific functions more broadly expressed TFs may employ. To address this, we combined a TF-focused CRISPR screen with epigenomic and transcriptional profiling of human neural crest cells. This approach unbiasedly identified several key regulators of human neural crest cell development, including the ubiquitous AP-1 transcription factor complex. Functional characterization of AP-1 demonstrated it is a major regulator of neural crest identity, working with the cell type specific TF, TFAP2A, to shape the neural crest epigenome. Interestingly, overexpression of AP-1 and TFAP2A in human embryonic stem cells is sufficient to drive neural crest identity, suggesting a critical role for AP-1 in the transition from pluripotency to more specialized stem cell states. Furthermore, we demonstrate that AP-1 serves as a nuclear effector of FGF/MAPK signaling in human neural crest cells, a previously missing link between FGF signaling and neural crest development. Our results demonstrate signaling effectors carry out cell-type specific enhancer selection and may contribute to our efforts in engineering neural crest cells for the purpose of tissue repair and regeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212793 | GEO | 2023/08/25

REPOSITORIES: GEO

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