Manipulation of protein translation and stem cell self-renewal by CRISPR activation of rRNA transcription

• 成果类型: Article
• 署名作者: Wiesbeck, Maximilian; Alard, Emilie L.; Merino, Florencia; Chowdhury, Niti; Egert, Luisa; Danese, Anna; Imhof, Simon; Iraci Borgia, Matilde; Rajan, Akshaya; Fernandez-Novel Marx, Nadine; Kepesidis, Edina; Koeferle, Anna; Cerron-Alvan, Luis Miguel; Vierl, Franziska; Truong, Thi-Tram; Thorwirth, Manja; Bilalli, Lorina; Santos Dias Mourao, Andre; Ninkovic, Jovica; Schieweck, Rico; Diefenbacher, Markus; Hauck, Stefanie M.; Trainor, Paul A.; Mardakheh, Faraz K.; Goetz, Magdalena; Stricker, Stefan H.
• 署名单位: University of Munich; University of Oxford; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; University of Luxembourg; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Stowers Institute for Medical Research; University of Kansas; University of Kansas Medical Center; University of Geneva; Boehringer Ingelheim
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aeh1348
• 发表日期: 2026-09-10
• 页码: eaeh1348
• 关键词: SPACER PROMOTERS; I TRANSCRIPTION; POLYMERASE I; dna; Nucleolus; pluripotency; enhancement; biogenesis; elongation; inhibition

摘要

Ribosomal RNA (rRNA) transcription rates vary during development, and their dysregulation is linked to diseases such as cancer and ribosomopathies. Owing to their high abundance and genomic redundancy, the functional significance of rRNA levels remains unclear. We developed TAPIR (Targeted Activation of Protein Translation), a CRISPR-based approach to elevate rRNA levels by inducing 47S ribosomal DNA transcription. TAPIR increased nucleolar size and enhanced protein synthesis, even in rapidly proliferating cells. In neural stem cells, elevated translation promoted self-renewal and proliferation in vitro and in vivo. Furthermore, TAPIR enabled the modeling and partial rescue of associated disease phenotypes. Our findings reveal that rRNA levels directly regulate translational output and that protein synthesis capacity can act as a key determinant of mammalian stem cell behavior.