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bioRxiv · 10.1101/2025.05.24.655549

Clonal lineage tracing and parallel multiomics profiling reveal transcriptional diversification induced by ARID1A deficiency

Miyata, K.·Yang, L.·Yang, Y.·Kumegawa, K.·Maruyama, R.
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Abstract

Phenotypic heterogeneity among genetically identical cancer cells underpins tumor progression and therapy resistance. However, the mechanism of epigenetic dysregulation that drives such divergence remains unclear. This study introduces integrated multimodal experimental platform specialized in analyzing inter/intraclonal heterogeneity (IMPACH), a scalable platform that integrates lineage tracing, genetic perturbation, and multimodal single-cell analysis. Utilizing IMPACH, results revealed that loss of epigenetic regulators--particularly ARID1A--enhances transcriptomic and epigenetic heterogeneity under controlled conditions. ARID1A deficiency promotes stochastic chromatin opening and induces an atypical gene expression program associated with poor clinical outcomes. Despite increased epigenetic randomness, chromatin changes remain localized to regulatory elements, partially linked to SMARCA4 binding sites. These findings revealed that chromatin remodeling defects promote clonal diversification through both stochastic and constrained mechanisms. Thus, owing to its scalability and versatility, IMPACH provides a robust framework for elucidating how epigenetic perturbations shape cellular heterogeneity in cancer.

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Miyata, K., Yang, L., Yang, Y., Kumegawa, K., Maruyama, R.. 2025-05-28. Clonal lineage tracing and parallel multiomics profiling reveal transcriptional diversification induced by ARID1A deficiency. https://doi.org/10.1101/2025.05.24.655549

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