Integrative discovery and functional dependency mapping uncover essential chimeric RNAs in the active transcriptome
7 affiliations
- 1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
- 2Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
- 3Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
- 4State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University, Zhengzhou 450052, China.
- 5Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
- 6Comprehensive Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
- 7Center for RNA Science and Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Abstract
Chimeric RNAs are a class of molecules defined as RNA transcripts containing genetic information for multiple genes. While their expression patterns across tissue types and disease states have been well documented, the biological function of these transcripts remains poorly understood. In this study, we developed an integrative prediction pipeline to establish an atlas of 569,640 chimeric RNAs across 1019 cancer cell lines. Leveraging this resource, we performed a systematic functional dependency screen by integrating our predictions with perturbation datasets from The Cancer Dependency Map project. This approach moves beyond prediction to identifying high-confidence functional chimeric RNAs essential for cellular processes, including a subset of recurrent chimeric transcripts generated by cis-splicing of adjacent genes. We demonstrate that depletion of selected candidate chimeras disrupts cell cycle progression and cellular fitness and that these transcripts are frequently dysregulated in primary breast tumors. Together, these results demonstrate that chimeric RNAs constitute a previously underappreciated layer of gene expression, expanding the functional genome beyond conventional genetics.
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BibTeX
@article{lalani2026integrative,
title = {{Integrative discovery and functional dependency mapping uncover essential chimeric RNAs in the active transcriptome}},
author = {Samir Lalani and Samuel Haddox and Kendall Bromley and Shafaque Zahra and Marina Wang and Mason Ingram and Sehajroop Gadh and Shriya Gunalan and Sulun Ke and Qiong Wang and Fujun Qin and Eric Hendrickson and Anja Bielinsky and Hui Li},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aei0901},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aei0901},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integrative discovery and functional dependency mapping uncover essential chimeric RNAs in the active transcriptome
AU - Samir Lalani
AU - Samuel Haddox
AU - Kendall Bromley
AU - Shafaque Zahra
AU - Marina Wang
AU - Mason Ingram
AU - Sehajroop Gadh
AU - Shriya Gunalan
AU - Sulun Ke
AU - Qiong Wang
AU - Fujun Qin
AU - Eric Hendrickson
AU - Anja Bielinsky
AU - Hui Li
PY - 2026
DA - 2026/10/30
JO - Science Advances
DO - 10.1126/sciadv.aei0901
UR - https://www.science.org/doi/abs/10.1126/sciadv.aei0901
AB - Chimeric RNAs are a class of molecules defined as RNA transcripts containing genetic information for multiple genes. While their expression patterns across tissue types and disease states have been well documented, the biological function of these transcripts remains poorly understood. In this study, we developed an integrative prediction pipeline to establish an atlas of 569,640 chimeric RNAs across 1019 cancer cell lines. Leveraging this resource, we performed a systematic functional dependency screen by integrating our predictions with perturbation datasets from The Cancer Dependency Map project. This approach moves beyond prediction to identifying high-confidence functional chimeric RNAs essential for cellular processes, including a subset of recurrent chimeric transcripts generated by cis-splicing of adjacent genes. We demonstrate that depletion of selected candidate chimeras disrupts cell cycle progression and cellular fitness and that these transcripts are frequently dysregulated in primary breast tumors. Together, these results demonstrate that chimeric RNAs constitute a previously underappreciated layer of gene expression, expanding the functional genome beyond conventional genetics.
SN - 2375-2548
ER -