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:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 27. Date of Electronic Publication: 2023 Sep 27.
DOI:	10.1101/2023.09.27.559752
Abstrakt:	About 100 genes have been associated with significantly increased risks of autism spectrum disorders (ASD) with an estimate of ~1000 genes that may be involved. The new challenge now 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 use single cell RNA-seq analysis to study one of the top risk gene, CHD8 , in cerebral organoids, which models early neural development. We identify 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 the CHD8 knockout and their isogenic controls uncover thousands of differentially expressed genes, which are enriched with function related to neural and brain development, with genes and pathways previously implicated in ASD, but surprisingly not for Schizophrenia and intellectual disability risk genes. The comparisons also find cell composition changes, indicating potential altered neural differential trajectories upon CHD8 reduction. Moreover, we find that cell-cell communications are affected in the CHD8 knockout organoids, including the interactions between neural and glial cells. Taken together, our results provide new data for understanding CHD8 functions in the early stages of neural lineage development and interaction. Competing Interests: Competing interests None to declare.
Databáze:	MEDLINE
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