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

Janine Sengstack, Jiashun Zheng, Turan Aghayev, Gregor Bieri, Michael Mobaraki, Jue Lin, Changhui Deng, Saul A Villeda, Hao Li

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143. · pubmed

Paper

Abstract

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.

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Research summary

Single transcription factor perturbations can drive cellular and tissue rejuvenation by reversing aging-associated changes. This paper is relevant as it addresses the root causes of aging through transcriptional reprogramming, aiming to promote rejuvenation rather than merely treating age-related symptoms.

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