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Peer-reviewedCC BYScience Advances

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

  • Kenichi Miyata1,2
  • Liying Yang1
  • Yuxiao Yang1
  • Kohei Kumegawa3
  • Reo Maruyama1,3
  1. 1Division of Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
  2. 2Cancer Cell Communication Project, NEXT-Ganken Program, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
  3. 3Cancer Cell Diversity Project, NEXT-Ganken Program, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
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Abstract

Transcriptional heterogeneity drives malignant progression, yet how it emerges within tumors remains unclear. By combining genetic perturbation and lineage tracing with parallel single-cell multiomics, we tracked the consequences of ARID1A loss within individual clonal lineages. ARID1A deficiency increased transcriptional variability both within and across clones, recurrently giving rise to diverse transcriptional profiles that did not converge on a common, coordinated pattern. This variability was accompanied by broadened chromatin accessibility at normally silenced loci and depended on residual SMARCA4 activity. Clones in which this variability was prominent showed no growth advantage under standard conditions but were preferentially recovered under specific environmental stresses and during lung colonization, a context dependence consistent with bet-hedging. Our findings suggest that loss of an epigenetic regulator can promote tumor evolution by relaxing transcriptional constraints and widening the range of phenotypes accessible to a clonal lineage, rather than by imposing a single fixed phenotype.

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Cite

BibTeXRIS
BibTeX
@article{miyata2026clonal,
  title = {{Clonal lineage tracing and parallel multiomics profiling reveal transcriptional heterogeneity induced by ARID1A deficiency}},
  author = {Kenichi Miyata and Liying Yang and Yuxiao Yang and Kohei Kumegawa and Reo Maruyama},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aed7880},
  url = {https://www.science.org/doi/10.1126/sciadv.aed7880},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Clonal lineage tracing and parallel multiomics profiling reveal transcriptional heterogeneity induced by ARID1A deficiency
AU  - Kenichi Miyata
AU  - Liying Yang
AU  - Yuxiao Yang
AU  - Kohei Kumegawa
AU  - Reo Maruyama
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aed7880
UR  - https://www.science.org/doi/10.1126/sciadv.aed7880
AB  - Transcriptional heterogeneity drives malignant progression, yet how it emerges within tumors remains unclear. By combining genetic perturbation and lineage tracing with parallel single-cell multiomics, we tracked the consequences of ARID1A loss within individual clonal lineages. ARID1A deficiency increased transcriptional variability both within and across clones, recurrently giving rise to diverse transcriptional profiles that did not converge on a common, coordinated pattern. This variability was accompanied by broadened chromatin accessibility at normally silenced loci and depended on residual SMARCA4 activity. Clones in which this variability was prominent showed no growth advantage under standard conditions but were preferentially recovered under specific environmental stresses and during lung colonization, a context dependence consistent with bet-hedging. Our findings suggest that loss of an epigenetic regulator can promote tumor evolution by relaxing transcriptional constraints and widening the range of phenotypes accessible to a clonal lineage, rather than by imposing a single fixed phenotype.
SN  - 2375-2548
ER  -