Developmental convergence and divergence in human stem cell models of autism

Jan 29, 2026Nature

Similarities and Differences in Brain Development Using Human Stem Cell Models of Autism

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Abstract

A collection of 70 human induced pluripotent stem (hiPS) cell lines representing 8 ASD-associated mutations was used to study gene expression changes over 100 days.

More than 100 genes linked to autism spectrum disorder (ASD) have been identified with rare mutations.
Distinct mutations showed specific changes in gene expression at early developmental stages, but converged on shared transcriptional changes over time.
A common network of RNA and protein interactions was found to be enriched in ASD risk genes, suggesting a unified mechanism of dysregulation.
CRISPR-Cas9 screening confirmed the role of identified transcriptional regulators in influencing downstream gene expression changes.
These findings support the idea that genetic risk for ASD may converge on similar pathways during neurodevelopment.

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Two decades of genetic studies in autism spectrum disorder (ASD) have identified more than 100 genes harbouring rare risk mutations. Despite this substantial heterogeneity, transcriptomic and epigenetic analyses have identified convergent patterns of dysregulation across the ASD postmortem brain. To identify shared and distinct mechanisms of ASD-linked mutations, we assembled a large patient collection of human induced pluripotent stem (hiPS) cells, consisting of 70 hiPS cell lines after stringent quality control representing 8 ASD-associated mutations, idiopathic ASD, and 20 lines from non-affected control individuals. Here we used these hiPS cell lines to generate human cortical organoids, profiling by RNA sequencing at four distinct time points up to 100 days after in vitro differentiation. Early time points harboured the largest mutation-specific changes, but different mutations converged on shared transcriptional changes as development progressed. We identified a shared RNA and protein interaction network, which was enriched in ASD risk genes and predicted to drive the observed downstream changes in gene expression. CRISPR-Cas9 screening of these candidate transcriptional regulators in induced human neural progenitors validated their downstream convergent molecular effects. These data illustrate how risk associated with genetically defined forms of ASD can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing new insight into the convergent impact of ASD genetic risk on human neurodevelopment. 1-13 14,15-17

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Developmental convergence and divergence in human stem cell models of autism

Abstract

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