Molecular and network disruptions in neurodevelopment uncovered by single cell transcriptomics analysis of CHD8 heterozygous cerebral organoids.

Autor:	Astorkia M; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA., Liu Y; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA., Pedrosa EM; Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine, Bronx, NY, USA., Lachman HM; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.; Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine, Bronx, NY, USA.; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA., Zheng D; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.; Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
Jazyk:	angličtina
Zdroj:	Heliyon [Heliyon] 2024 Jul 18; Vol. 10 (14), pp. e34862. Date of Electronic Publication: 2024 Jul 18 (Print Publication: 2024).
DOI:	10.1016/j.heliyon.2024.e34862
Abstrakt:	More than 100 genes have been associated with significantly increased risks of autism spectrum disorders (ASD) with an estimate of ∼1000 genes that may contribute. The new challenge is to investigate the molecular and cellular functions of these genes during neural and brain development, and then even more challenging, to link the altered molecular and cellular phenotypes to the ASD clinical manifestations. In this study, we used single-cell RNA-seq analysis to study one of the top risk genes, CHD8 , in cerebral organoids, which models early neural development. We identified 21 cell clusters in the organoid samples, representing non-neuronal cells, neural progenitors, and early differentiating neurons at the start of neural cell fate commitment. Comparisons of the cells with one copy of a CHD8 knockout allele, generated by CRISPR/Cas9 editing, and their isogenic controls uncovered thousands of differentially expressed genes, which were enriched with functions related to neural and brain development, cilium organization, and extracellular matrix organization. The affected genes were also enriched with genes and pathways previously implicated in ASD, but surprisingly not for schizophrenia and intellectual disability risk genes. The comparisons also uncovered cell composition changes, indicating potentially altered neural differential trajectories upon CHD8 reduction. Moreover, we found that cell-cell communications were affected in the CHD8 knockout organoids, including the interactions between neural and glial cells. Taken together, our results provide new data and information for understanding CHD8 functions in the early stages of neural lineage development and interaction. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2024 The Authors.)
Databáze:	MEDLINE
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