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Chemically Induced Chromosomal Interaction (CICI) method to study chromosome dynamics and its biological roles

Manyu Du,F. Zou,Yi Li,Yujie Yan,Lu Bai

Published 2022 in Nature Communications

ABSTRACT

Numerous intra- and inter-chromosomal contacts have been mapped in eukaryotic genomes, but it remains challenging to link these 3D structures to their regulatory functions. To establish the causal relationships between chromosome conformation and genome functions, we develop a method, Chemically Induced Chromosomal Interaction (CICI), to selectively perturb the chromosome conformation at targeted loci. Using this method, long-distance chromosomal interactions can be induced dynamically between intra- or inter-chromosomal loci pairs, including the ones with very low Hi-C contact frequencies. Measurement of CICI formation time allows us to probe chromosome encounter dynamics between different loci pairs across the cell cycle. We also conduct two functional tests of CICI. We perturb the chromosome conformation near a DNA double-strand break and observe altered donor preference in homologous recombination; we force interactions between early and late-firing DNA replication origins and find no significant changes in replication timing. These results suggest that chromosome conformation plays a deterministic role in homology-directed DNA repair, but not in the establishment of replication timing. Overall, our study demonstrates that CICI is a powerful tool to study chromosome dynamics and 3D genome function. Methods to selectively manipulate specific long-distance chromosomal interactions are limited. Here the authors develop a method called Chemically Induced Chromosomal Interaction (CICI) to engineer interactions and demonstrate that 3D conformation plays a causal role in establishing donor DNA preference during DNA repair.

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