Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41512022.
- Also identified by DOI 10.1073/pnas.2515183123 and PMC identifier 12799168.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Rejuvenation
- Transcription Factors