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Decoding the MYC locus reveals a druggable ultraconserved RNA element
Peiguo Shi1,2,3, Feiyue Yang1,2,3, Fnu Tala3,4
1Division of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
Biorxiv : the Preprint Server for Biology
|February 9, 2026
Summary
Most essential base pairs in the human MYC gene are noncoding. A 3' untranslated region RNA element is vital for MYC-driven cancers and a potential therapeutic target.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Biology
Background:
- The human genome contains many noncoding sequences with unknown functions.
- Understanding the distribution of genetic information between coding and noncoding regions is crucial.
Purpose of the Study:
- To map the functional landscape of the human MYC locus at base-pair resolution.
- To identify essential noncoding elements and their role in MYC-driven cancers.
Main Methods:
- CRISPR saturation mutagenesis with SpRY-Cas9.
- Functional fitness landscape mapping of the MYC locus.
- Antisense oligonucleotide targeting of a specific RNA element.
Main Results:
- 67% of functionally essential base pairs in the MYC locus are noncoding.
- Noncoding elements' phenotypic impact inversely correlates with evolutionary conservation.
- An ultraconserved 3' UTR RNA element is essential for MYC-dependent cancer cells.
- Targeting this RNA element selectively eliminates cancer cells by suppressing MYC function.
Conclusions:
- Noncoding sequences carry significant functional genetic information.
- A comprehensive fitness map of the MYC locus was generated.
- A therapeutically actionable RNA element targeting MYC-driven cancer was identified.
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