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PreprintCC BY-NCbioRxiv

Systematic CRISPRi perturbation of 1,408 autism risk genes maps multilevel transcriptional convergence in human cortical neurons

  • A. Gogate
  • W.-C. Chen
  • M. Nzima
  • C. Takeuchi
  • H. Zhao
  • L. Wang
  • S. Sivakumar
  • M. Deng
  • K. Kaur
  • W. L. Kraus
  • N. V. Munshi
  • G. C. Hon
1 more authors
  • M. H. Chahrour1
  1. 1UT Southwestern Medical Center
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Abstract

Genetic heterogeneity in autism spectrum disorder (ASD) complicates the identification of shared molecular pathways amenable to therapeutic intervention. Here, we perform a CRISPRi Perturb-seq screen targeting 1,408 ASD risk genes in human embryonic stem cell-derived immature cortical neurons and profile the resulting transcriptomic effects by single-cell RNA sequencing. We identify 215 ASD risk genes whose repression induces significant global transcriptomic dysregulation. Leveraging this functional atlas, we characterize candidate genes based on transcriptional similarity to established ASD hub genes. We identify gene programs recurrently dysregulated across perturbations, anchored by processes governing microtubule dynamics, neuron differentiation, cell migration, and transmembrane transport. We further identify CHAMP1 as a previously unrecognized regulator of Wnt signaling and define specific ASD risk genes that modulate the rate of cortical neuron differentiation. Analysis of differentially expressed genes reveals both convergent and perturbation-specific downstream transcriptional responses. Together, these findings provide a multilevel map of transcriptomic convergence in ASD and establish a framework for identifying both pathway-level and genotype-specific therapeutic strategies.

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Cite

BibTeXRIS
BibTeX
@misc{gogate2026systematic,
  title = {{Systematic CRISPRi perturbation of 1,408 autism risk genes maps multilevel transcriptional convergence in human cortical neurons}},
  author = {A. Gogate and W.-C. Chen and M. Nzima and C. Takeuchi and H. Zhao and L. Wang and S. Sivakumar and M. Deng and K. Kaur and W. L. Kraus and N. V. Munshi and G. C. Hon and M. H. Chahrour},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.02.748925},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.02.748925v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - Systematic CRISPRi perturbation of 1,408 autism risk genes maps multilevel transcriptional convergence in human cortical neurons
AU  - A. Gogate
AU  - W.-C. Chen
AU  - M. Nzima
AU  - C. Takeuchi
AU  - H. Zhao
AU  - L. Wang
AU  - S. Sivakumar
AU  - M. Deng
AU  - K. Kaur
AU  - W. L. Kraus
AU  - N. V. Munshi
AU  - G. C. Hon
AU  - M. H. Chahrour
PY  - 2026
DA  - 2026/09/02
PB  - bioRxiv
DO  - 10.64898/2026.09.02.748925
UR  - https://www.biorxiv.org/content/10.64898/2026.09.02.748925v1
AB  - Genetic heterogeneity in autism spectrum disorder (ASD) complicates the identification of shared molecular pathways amenable to therapeutic intervention. Here, we perform a CRISPRi Perturb-seq screen targeting 1,408 ASD risk genes in human embryonic stem cell-derived immature cortical neurons and profile the resulting transcriptomic effects by single-cell RNA sequencing. We identify 215 ASD risk genes whose repression induces significant global transcriptomic dysregulation. Leveraging this functional atlas, we characterize candidate genes based on transcriptional similarity to established ASD hub genes. We identify gene programs recurrently dysregulated across perturbations, anchored by processes governing microtubule dynamics, neuron differentiation, cell migration, and transmembrane transport. We further identify CHAMP1 as a previously unrecognized regulator of Wnt signaling and define specific ASD risk genes that modulate the rate of cortical neuron differentiation. Analysis of differentially expressed genes reveals both convergent and perturbation-specific downstream transcriptional responses. Together, these findings provide a multilevel map of transcriptomic convergence in ASD and establish a framework for identifying both pathway-level and genotype-specific therapeutic strategies.
ER  -