Gene syntax defines supercoiling-mediated transcriptional feedback

• 成果类型: Article
• 署名作者: Johnstone, Christopher P.; Love, Kasey S.; Kabaria, Sneha R.; Jones, Ross D.; Blanch-Asensio, Albert; Ploessl, Deon S.; Peterman, Emma L.; Lee, Rachel; Yun, Jiyoung; Oakes, Conrad G.; Mummery, Christine L.; Davis, Richard P.; DeKosky, Brandon J.; Zandstra, Peter W.; Galloway, Kate E.
• 署名单位: Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); University of British Columbia; University of British Columbia; California Institute of Technology; Leiden University; Leiden University - Excl LUMC; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adw1925
• 发表日期: 2026-04-30
• 页码: eadw1925
• 关键词: dna; expression; genome; promoters; context; interference; orientation; DISCOVERY; TOPOLOGY; IMPACT

摘要

Gene syntax-the order and arrangement of genes and their regulatory elements-shapes the dynamic coordination of both natural and synthetic gene circuits. Transcription at one locus perturbs the transcription of adjacent genes, but the molecular basis of this effect remains poorly understood. In this work, we show that supercoiling-mediated feedback arises from transcription and regulates expression of adjacent genes in a syntax-specific manner. Using a suite of assays, we measured syntax- and induction-dependent formation of chromatin structures in human induced pluripotent stem cells. Applying syntax as a design parameter, we built and improved compact gene circuits, tuning the expression mean, noise, and stoichiometry across delivery methods and cell types. Integrating supercoiling mediated feedback into models of gene regulation will expand our understanding of native and synthetic systems.