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Shi, P.; Yang, F.; FNU, T.; Huang, W.; Aparicio, A. O.; Kalicki, C. H.; Trehan, A.; Murphy, M. R.; Rotlevi, E. R.; Xing et al.
The human genome is dominated by noncoding sequences, most of which are poorly conserved across species. How genetic information is distributed between coding and noncoding regions remains a fundamental unresolved question. Using CRISPR saturation mutagenesis at base-pair resolution, we mapped the functional fitness landscape of the 10-kb human MYC locus with a near-PAMless, high-fidelity SpRY-Cas9. This unbiased interrogation revealed that the majority (67%) of functionally essential base-pairs in this locus are noncoding. Paradoxically, the phenotypic impact of noncoding sequences correlates inversely with evolutionary conservation, driven in part by rapidly diverging cis-regulatory DNA elements that remain functionally constrained in humans. Within this landscape, we identified an ultraconserved RNA element in the 3 untranslated region (UTR) that is indispensable for MYC-dependent cancer cells. Remarkably, steric-blocking antisense oligos targeting this RNA element selectively eliminate MYC-addicted cancer cells by suppressing MYC function without reducing MYC abundance. Mechanistically, this 3' UTR element promotes perinuclear localization of MYC mRNA and efficient nuclear import of the short-lived MYC protein, enabling its function as a nuclear transcription factor. Together, these findings highlight noncoding sequences as major carriers of functional genetic information, provide a comprehensive fitness map of the MYC locus, and uncover a therapeutically actionable RNA element that disables MYC-driven cancer.
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CD4⁺ T cells confer transplantable rejuvenation via Rivers of telomeres
Lanna, A.; Valvo, S.; Dustin, M.; Rinaldi, F.
Using a GPT-5-driven autonomous lab to optimize the cost and titer of cell-free protein synthesis
Smith, A. A.; Wong, E. L.; Donovan, R. C.; Chapman, B. A.; Harry, R.; Tirandazi, P.; Kanigowska, P.; Gendreau, E. A.; Dahl, R. H.; Jastrzebski, M.; Cortez, J. E.; Bremner, C. J.; Hemuda, J. C. M.; Dooner, J.; Graves, I.; Karandikar, R.; Lionetti, C.; Christopher, K.; Consiglio, A. L.; Tran, A.; McCusker, W.; Nguyen, D. X.; Nunes da Silva, I. B.; Bautista-Ayala, A. R.; McNerney, M. P.; Atkins, S.; McDuffie, M.; Serber, W.; Barber, B. P.; Thanongsinh, T.; Nesson, A.; Lama, B.; Nichols, B.; LaFrance, C.; Nyima, T.; Byrn, A.; Thornhill, R.; Cai, B.; Ayala-Valdez, L.; Wong, A.; Che, A. J.; Thavaraj
A Single-Cell and Spatial 3D Multi-omic Atlas of Developing Human Basal Ganglia and Inhibitory Neurons
Heffel, M. G.; Xu, H.; Pastor-Alonso, O.; Li, X.; Baig, M. S.; Irfan Ghoor, R.; Li, R.; Kern, C.; Kum, J.; Zhang, Y.; Paino, J.; Tsai, M. J.; Tai, C.-Y.; Tucker, G.; Zhao, Z.; Hou, A.; von Behren, Z.; Bhade, M.; Li, S.; Sandoval, K.; Scholes, J.; Codrea, F.; Calimlim, J.; Liao, E. K.; Leung, G.; Kim, J.; Eskin, E.; Flint, J.; Cotter, J. A.; Pasaniuc, B.; Bintu, B.; Zhu, Q.; Mukamel, E. A.; Ernst, J.; Paredes, M. F.; Luo, C.
Prediction of transformative breakthroughs in biomedical research
Davis, M. T.; Busse, B. L.; Arabi, S.; Meyer, P.; Hoppe, T. A.; Meseroll, R. A.; Hutchins, B. I.; Willis, K. A.; Santangelo, G. M.