264: Single-TF rejuvenation: EZH2, E2F3, STAT3, ZFX identified by TRDP/Perturb-seq rejuvenate human fibroblasts and mouse liver

Sengstack J et al., Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2515183123 - TRDP with Perturb-seq in human fibroblasts found that manipulating TFs (EZH2, E2F3, STAT3, ZFX) reversed aging hallmarks, and EZH2 overexpression rejuvenated aged mouse livers. Key terms: EZH2, E2F3, Perturb-seq, liver rejuvenation, transcription factor.

Study Highlights:
The study used passaged human neonatal dermal fibroblasts and aged mouse liver as model systems and applied the Transcriptional Rejuvenation Discovery Platform (TRDP) with Perturb-seq and CRISPRa/CRISPRi screens. Overexpressing E2F3 or EZH2 and repressing STAT3 or ZFX reversed global gene expression toward earlier passage states and ameliorated cellular aging hallmarks including increased proliferation, proteasome activity, and mitochondrial function. In aged mice, AAV8-mediated liver-specific EZH2 overexpression (log2fc ≈ 2.9) reversed thousands of age-associated gene changes (R_rej = -0.42), reduced steatosis and fibrosis, and improved glucose tolerance. Downstream transcriptional programs converged across perturbations, suggesting shared molecular requirements for cellular and tissue rejuvenation.

Conclusion:
Single transcription factor perturbations identified by TRDP can reverse cellular aging hallmarks in human fibroblasts and, in the case of EZH2 overexpression, partially rejuvenate aged mouse liver with improved histology and glucose tolerance.

Music:
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Article title:
Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation

First author:
Sengstack J

Journal:
Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2515183123

DOI:
10.1073/pnas.2515183123

Reference:
Sengstack J, Li H, Aghayev T, Bier G, Mobaraki M, Zheng J, Lin J, Deng C, Villeda SA, et al. Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2515183123. Published January 9, 2026. https://doi.org/10.1073/pnas.2515183123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections describing the TRDP platform, identification of four rejuvenating TF perturbations, in vitro cellular aging hallmarks, in vivo liver experiments with EZH2, safety considerations, and broader implications of aging as a programmable, reversible state.
- transcript topics: TRDP platform and Perturb-seq workflow; Top rejuvenating TF perturbations: E2F3, EZH2, STAT3, ZFX; In vitro reversal of aging hallmarks in late-passage fibroblasts; In vivo liver rejuvenation in aged mice via EZH2 overexpression; Cancer risk considerations and mesenchymal drift; Broader implications and potential organ-wide applications of TRDP

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal