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Researchers conducted a large-scale time-resolved CRISPR screening study of 400 genes linked to congenital heart disease using cardioids (heart organoids), profiling nearly one million cells across seven days of development. They found that gene perturbation effects are highly stage-dependent, with most disease-linked genes acting during early progenitor stages rather than later differentiation, and that the timing of gene function often differs from when the gene is expressed. The study also identified new candidate cardiac regulators and revealed how perturbation effects reorganize through developmental progression.
Why it matters
This work provides crucial insights into when and how genetic mutations cause congenital heart disease during human heart development, information that cannot be obtained from patient data or static tissue atlases. The systematic dataset could enable development of computational models to predict how genetic variants affect heart development at different stages, potentially improving genetic counseling and identifying therapeutic intervention windows.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Congenital heart disease (CHD) originates during early embryogenesis, yet when disease genes act cannot be determined from existing data. Human fetal heart atlases lack critical time points, and perturbation screens that systematically assess gene function currently profile at most a few time points. Here we combined single-cell CRISPR screening of 400 disease-relevant genes in cardioids, sampled daily over seven developmental days (~975,000 cells), with a matched multiome atlas. Perturbation phenotypes were strongly dependent on developmental stage. Perturbations that reshaped cell-fate allocation or gene expression were enriched for CHD-linked genes, and most acted already during progenitor stages. Timing was largely independent of the target gene’s own expression, marking instead when a cell state became functionally dependent on it, and some effects persisted after expression declined. Consensus gene regulatory networks integrating perturbation and multiome data recovered stage-specific regulators and nominated HOXB2 and HOXB3 as candidate cardiac regulators. Many perturbations converged on shared downstream programmes, which were reorganised through differentiation. Effects correlated in progenitors were maintained in differentiated cells, split into distinct programmes, converged with other perturbations or disappeared entirely, indicating that gene function is highly context dependent. Beyond advancing our understanding of the developmental regulatory logic underlying CHD, our work provides a resource for developing context-dependent models for in silico prediction of perturbation effects.