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Chromosome-Specific Aneuploidy Engineering via dCas9-Induced Centromeric Chromatin Relaxation

de Hugang Feng, Daqi Deng, Rashmi Dahiya, Libin Wang, Jingkun Zeng, Benjy Jek Yang Tan, Fiona Byrne, Scott T. C. Shepherd, Jiahao Wang, Sarah C. Johnson, Alison Harrod, Karen A. Lane, Annika Fendler, Anne-Laure Cattin, Zayd Tippu, Meilun Nie, Yiming Zhao, Ruijia Wang, Wei Ai, Omar Bouricha, Taja Barber, Yuliia Dovga, Yihan Xu, Yimeng Xu, Liani G. Devito, Lyn Healy, Zhen Sun, Weiming Shen, Hongye Wang, Eugénie S. Lim, Samuel M. O’Toole, Scott Akker, William M. Drake, Haojie Jin, Jessica A. Downs, Sarah E. McClelland, John F. X. Diffley, Peter Ly e Samra Turajlic

Publicado: 27 de abril de 2025
Servidor: bioRxiv
DOI: 10.1101/2025.04.25.650684

Resumo

Aneuploidy, characterised by an imbalanced chromosome copy number, is the cause of chromosomal disorders¹as well as a hallmark of cancer². Beyond pathological conditions, recent studies highlight the presence of lineage-specific recurrent aneuploidies in normal tissues^3–5. Despite its prevalence, the functional significance of aneuploidies in cellular dysfunction and diseases remains elusive, hindered by experimental challenges in engineering relevant aneuploidy models for mechanistic investigation. Here, we discover that the centromeric recruitment of catalytically dead Cas9 (dCas9) induces efficient chromosome-specific mis-segregation, applicable to all 24 human chromosomes. We show that the mis-segregation phenotype is driven by dCas9-induced kinetochore chromatin relaxation, resulting in whole chromosome aneuploidy or arm-level aneuploidy with centromeric breakage. In induced pluripotent stem cells, we demonstrate aneuploidy manipulation for chromosome 13, 21, X, and Y. In primary renal epithelial cells, we engineered chromosome 3(p) loss, the tumour-initiating event in clear cell renal cell carcinoma (ccRCC)⁶.. Overall, we describe a simple, efficient, and versatile approach for chromosome-specific aneuploidy generation that can facilitate preclinical aneuploid model development for functional interrogation of aneuploidy.

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Avaliação PREreview de Joseph Biggane et al.

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Review coordinated via ASAPbio’s crowd preprint review
This review reflects comments and contributions by Joseph Biggane and Andreia Pereira. Review synthesized by Joseph Biggane.
This study investigated a novel method for manipulating ploidy in human immortalized, primary, and induced pluripotent…

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Avaliações PREreview de Chromosome-Specific Aneuploidy Engineering via dCas9-Induced Centromeric Chromatin Relaxation

1 Avaliação PREreview