This repository contains the code used for the paper Early Developmental Origins of Cortical Disorders Modeled in Human Neural Stem Cells.

bioarxiv Early Developmental Origins of Cortical Disorders Modeled in Human Neural Stem Cells
Xoel Mato-Blanco, Suel-Kee Kim, Alexandre Jourdon, Shaojie Ma, Andrew T.N. Tebbenkamp, Fuchen Liu, Alvaro Duque, Flora M. Vaccarino, Nenad Sestan, Carlo Colantuoni, Pasko Rakic, Gabriel Santpere, Nicola Micali
bioRxiv 2024.06.14.598925; doi: https://doi.org/10.1101/2024.06.14.598925

Analyses

Each folder under analyses contains the code used for the different analyses performed in the paper. The README.md file in each folder provides a brief description of the analyses performed in that folder.

The main analysis categories include:

• disease_characterization: Characterization of disease gene expression and enrichment in in vitro NSC differentiation time course.
• rcistarget: Identification of potential regulators using RcisTarget based on co-expression modules.
• annotate_progenitors: Annotation of progenitor cell types.
• celloracle: Gene Regulatory Network inference using CellOracle.
• asd_analyses: Specific analyses related to Autism Spectrum Disorder datasets.
• Braun_analyses: Analysis of the Braun et al. 2023 fetal brain dataset, including re-annotation, disease gene expression, and EWCE enrichment.
• Complexity: Analysis of transcriptome and GRN complexity.
• DiseaseenrichmentinCOGRN: Enrichment testing of disease genes within CellOracle GRNs.
• JourdonpairwiseDE_comparison: Pairwise differential expression analysis on the Jourdon et al. 2023 dataset to assess expression variability.

Data

Relevant data is provided as supplementary tables accompanying our main publication. Please refer to the publication for these resources. We provide our annotation table specifically employed for the Braun dataset within this DATA directory.

Core Datasets

• Our newly generated datasets, including scRNA-seq and bulk RNA-seq from Control and ASD iPSC lines were deposited in the GEO public database, with accession codes GSE271968 and GSE271965, respectively.

• All datasets utilized in our analyses, including processed data and relevant metadata, are publicly available through our Neuroscience Multi-Omic (NeMO) Archive website. We encourage users to visit the NeMO portal for comprehensive access and browse these data online:

  • Individual gene expression (NeMO/genes).
  • Expression of disease gene lists (NeMO/diseasegenesets).
  • GWCoGAPS patterns from Micali et al., 2020 NSC progression (NeMO/CoGAPS).
  • GWCoGAPS patterns from Micali et al., 2020 neuronal differentiation (NeMO/CoGAPSII).
  • Disease Regulons (NeMO/DisRegulons).
  • Temporal Regulons (NeMO/TempRegulons).
  • PCA of DIV8 scRNA-seq data (NeMO/PCA).

• Alternatively, the datasets can be accessed as described in their respective publications.

  • Single-cell RNA-seq, first trimester human brain
    Braun et al., 2023: EGA EGAS00001004107
  • Bulk RNA-seq, hiPSC neuronal differentiation
    Burke et al., 2020: NCBI SRA BioProject PRJNA596331
  • Single-cell RNA-seq, spatiotemporal human cortex development
    Nowakowski et al., 2017: dbGaP phs000989.v3.p1
  • Bulk RNA-seq, mouse cortical projection neuron maturation (DeCoN)
    Molyneaux et al., 2015: GEO GSE63482
  • Single-nuclei RNA-seq, primate prefrontal cortex evolution
    Ma et al., 2022: GEO GSE207334
  • Single-cell RNA-seq, mouse radial glia differentiation trajectory
    Telley et al., 2019: GEO GSE118953
  • Single-cell RNA-seq and scATAC-seq, developing human cortex PCW16-24
    Trevino et al., 2021: GEO GSE162170
  • Single-cell RNA-seq and scATAC-seq, developing mouse cortex
    Noack et al., 2022: GEO GSE155677
  • RNA-seq, developing mouse brain
    La Manno et al., 2021: NCBI SRA BioProject PRJNA637987
  • Single-cell RNA-seq, developing macaque telencephalon
    Micali et al., 2023: GEO GSE226451
    
  • Fetal human cortex gene expression microarray
    Miller et al., 2014: BrainSpan Atlas Developmental Transcriptome
  • Single-nuclei RNA-seq and snATAC-seq, human prefrontal cortex across gestation to adulthood
    Herring et al., 2022: GEO GSE168408
  • Laser micro-dissected macaque developing cortex microarray
    Bakken et al., 2016: NIH Blueprint NHP Atlas
  • Bulk and single-cell RNA-seq, hNSC progression and differentiation
    Micali et al., 2020: GEO GSE144156, GEO GSE144157, GEO GSE144508
  • Bulk RNA-seq and epigenomic data, hNSC neural differentiation
    Ziller et al., 2015: GEO GSE62193
  • ASD and control brain organoids
    Jourdon et al., 2023: NIMH Data Archive Collection 3957

Citation

bibtex @article {Mato-Blanco2024.06.14.598925, author = {Mato-Blanco, Xoel and Kim, Suel-Kee and Jourdon, Alexandre and Ma, Shaojie and Tebbenkamp, Andrew T.N. and Liu, Fuchen and Duque, Alvaro and Vaccarino, Flora M. and Sestan, Nenad and Colantuoni, Carlo and Rakic, Pasko and Santpere, Gabriel and Micali, Nicola}, title = {Early Developmental Origins of Cortical Disorders Modeled in Human Neural Stem Cells}, elocation-id = {2024.06.14.598925}, year = {2024}, doi = {10.1101/2024.06.14.598925}, publisher = {Cold Spring Harbor Laboratory}, abstract = {The implications of the early phases of human telencephalic development, involving neural stem cells (NSCs), in the etiology of cortical disorders remain elusive. Here, we explored the expression dynamics of cortical and neuropsychiatric disorder-associated genes in datasets generated from human NSCs across telencephalic fate transitions in vitro and in vivo. We identified risk genes expressed in brain organizers and sequential gene regulatory networks across corticogenesis revealing disease-specific critical phases, when NSCs are more vulnerable to gene dysfunctions, and converging signaling across multiple diseases. Moreover, we simulated the impact of risk transcription factor (TF) depletions on different neural cell types spanning the developing human neocortex and observed a spatiotemporal-dependent effect for each perturbation. Finally, single-cell transcriptomics of newly generated autism-affected patient-derived NSCs in vitro revealed recurrent alterations of TFs orchestrating brain patterning and NSC lineage commitment. This work opens new perspectives to explore human brain dysfunctions at the early phases of development.One-sentence summary The temporal analysis of gene regulatory networks in human neural stem cells reveals multiple early critical phases associated with cortical disorders and neuropsychiatric traits.}, URL = {https://www.biorxiv.org/content/early/2024/06/14/2024.06.14.598925}, eprint = {https://www.biorxiv.org/content/early/2024/06/14/2024.06.14.598925.full.pdf}, journal = {bioRxiv} }