Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation

• 成果类型: Article
• 署名作者: Sengstack, Janine; Zheng, Jiashun; Aghayev, Turan; Bieri, Gregor; Mobaraki, Michael; Lin, Jue; Deng, Changhui; Villeda, Saul A.; Li, Hao
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2515183123
• 发表日期: 2026-01-13
• 页码: e2515183123
• 关键词: rejuvenation; replicative aging; Perturb-seq screening; liver aging; ezh2; hallmarks; E2F3; neurogenesis; senescence; polycomb; cancer; cells

摘要

Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging. Using a fibroblast-based model of human cell aging and Perturb-seq screening, we developed a systematic approach to identify single transcription factor (TF) perturbations that promote rejuvenation without dedifferentiation. Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging- increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.