Targeting PURPL RNA enabled rejuvenation of senescence cells via epigenetic reprogramming

Jie Wang; Xiao Yang; Xinyu Su; Wenkai Yi; Wei Sun; Jie Wei; Yong-Qiang Ning; Jian Yan

doi:10.1186/s12967-025-07208-5

Targeting PURPL RNA enabled rejuvenation of senescence cells via epigenetic reprogramming

Jie Wang (Co-first Author)
, Xiao Yang (Co-first Author)
, Xinyu Su (Co-first Author)
, Wenkai Yi
, Wei Sun
, Jie Wei
, Yong-Qiang Ning^*
, Jian Yan^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

2 Citations (Scopus)

3 Downloads (CityUHK Scholars)

Abstract

Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we identify the ageing-associated lncRNA PURPL as an epigenetic regulator that controls cellular rejuvenation through H3K9me3-mediated transcriptional silencing. CRISPRi-mediated PURPL depletion produces striking rejuvenation effects, resulting in restored youthful cell morphology, as well as suppression of senescence markers such as p21 and SA-β-gal. Conversely, PURPL overexpression accelerates cellular senescence, recapitulating the transcriptional and phenotypic hallmarks of ageing. Mechanistically, nuclear-localized PURPL regulates H3K9me3 deposition at 411 genomic loci including SERPINE1 (PAI-1) and EGR1, which are key senescence drivers. PURPL-mediated H3K9me3 loss at these loci derepresses their transcription, establishing a pro-senescence gene expression program. These findings reveal that PURPL is an epigenetic modulator of senescence and highlight its potential as a therapeutic target for age-related pathologies.

Original language	English
Article number	1127
Number of pages	16
Journal	Journal of Translational Medicine
Volume	23
Online published	17 Oct 2025
DOIs	https://doi.org/10.1186/s12967-025-07208-5
Publication status	Published - 17 Oct 2025

Bibliographical note

Funding

This work was supported by the following funding sources: Shenzhen Medical Research Fund (B2302027), National Natural Science Foundation of China (32270634), Natural Science Foundation of Guangdong Province (2024A1515012685), Shaanxi Innovation Capability Support Program (2024RS-CXTD-85), the Shaanxi Academy of Fundamental Sciences (Chemistry & Biology) (22JHZ009), the Research Grants Council of Hong Kong (11101022), Tung Biomedical Sciences Centre and City University of Hong Kong (9609317, 7006043).

Research Keywords

Cellular Senescence/genetics
Epigenesis, Genetic
Humans
RNA, Long Noncoding/genetics
Histones/metabolism
Cellular Reprogramming/genetics
Rejuvenation
Early Growth Response Protein 1/metabolism
Plasminogen Activator Inhibitor 1/metabolism
Gene Silencing
Transcription, Genetic
PURPL
Histone modification
H3K9me3
Long non-coding RNA

Publisher's Copyright Statement

This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

RGC Funding Information

RGC-funded

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10.1186/s12967-025-07208-5

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ASDC_Sub: Futian Research Project: Identification of Noncoding RNA Driving Epigenetic Changes During Cellular Senescence
YAN, J. (Principal Investigator / Project Coordinator) & ZHANG, J. (Co-Investigator)
1/04/24 → …
Project: Research
GRF: Unravelling the Molecular Mechanism of DNA Demethylation around CTCF Binding Sites in Mammalian Cells
YAN, J. (Principal Investigator / Project Coordinator)
1/01/23 → …
Project: Research

Cite this

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title = "Targeting PURPL RNA enabled rejuvenation of senescence cells via epigenetic reprogramming",

abstract = "Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we identify the ageing-associated lncRNA PURPL as an epigenetic regulator that controls cellular rejuvenation through H3K9me3-mediated transcriptional silencing. CRISPRi-mediated PURPL depletion produces striking rejuvenation effects, resulting in restored youthful cell morphology, as well as suppression of senescence markers such as p21 and SA-β-gal. Conversely, PURPL overexpression accelerates cellular senescence, recapitulating the transcriptional and phenotypic hallmarks of ageing. Mechanistically, nuclear-localized PURPL regulates H3K9me3 deposition at 411 genomic loci including SERPINE1 (PAI-1) and EGR1, which are key senescence drivers. PURPL-mediated H3K9me3 loss at these loci derepresses their transcription, establishing a pro-senescence gene expression program. These findings reveal that PURPL is an epigenetic modulator of senescence and highlight its potential as a therapeutic target for age-related pathologies. {\textcopyright} The Author(s) 2025.",

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AU - Wang, Jie

AU - Yang, Xiao

AU - Su, Xinyu

AU - Yi, Wenkai

AU - Sun, Wei

AU - Wei, Jie

AU - Ning, Yong-Qiang

AU - Yan, Jian

PY - 2025/10/17

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N2 - Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we identify the ageing-associated lncRNA PURPL as an epigenetic regulator that controls cellular rejuvenation through H3K9me3-mediated transcriptional silencing. CRISPRi-mediated PURPL depletion produces striking rejuvenation effects, resulting in restored youthful cell morphology, as well as suppression of senescence markers such as p21 and SA-β-gal. Conversely, PURPL overexpression accelerates cellular senescence, recapitulating the transcriptional and phenotypic hallmarks of ageing. Mechanistically, nuclear-localized PURPL regulates H3K9me3 deposition at 411 genomic loci including SERPINE1 (PAI-1) and EGR1, which are key senescence drivers. PURPL-mediated H3K9me3 loss at these loci derepresses their transcription, establishing a pro-senescence gene expression program. These findings reveal that PURPL is an epigenetic modulator of senescence and highlight its potential as a therapeutic target for age-related pathologies. © The Author(s) 2025.

AB - Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we identify the ageing-associated lncRNA PURPL as an epigenetic regulator that controls cellular rejuvenation through H3K9me3-mediated transcriptional silencing. CRISPRi-mediated PURPL depletion produces striking rejuvenation effects, resulting in restored youthful cell morphology, as well as suppression of senescence markers such as p21 and SA-β-gal. Conversely, PURPL overexpression accelerates cellular senescence, recapitulating the transcriptional and phenotypic hallmarks of ageing. Mechanistically, nuclear-localized PURPL regulates H3K9me3 deposition at 411 genomic loci including SERPINE1 (PAI-1) and EGR1, which are key senescence drivers. PURPL-mediated H3K9me3 loss at these loci derepresses their transcription, establishing a pro-senescence gene expression program. These findings reveal that PURPL is an epigenetic modulator of senescence and highlight its potential as a therapeutic target for age-related pathologies. © The Author(s) 2025.

KW - Cellular Senescence/genetics

KW - Epigenesis, Genetic

KW - Humans

KW - RNA, Long Noncoding/genetics

KW - Histones/metabolism

KW - Cellular Reprogramming/genetics

KW - Rejuvenation

KW - Early Growth Response Protein 1/metabolism

KW - Plasminogen Activator Inhibitor 1/metabolism

KW - Gene Silencing

KW - Transcription, Genetic

KW - PURPL

KW - Histone modification

KW - H3K9me3

KW - Long non-coding RNA

U2 - 10.1186/s12967-025-07208-5

DO - 10.1186/s12967-025-07208-5

M3 - RGC 21 - Publication in refereed journal

C2 - 41107828

SN - 1479-5876

VL - 23

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

M1 - 1127

ER -

Targeting PURPL RNA enabled rejuvenation of senescence cells via epigenetic reprogramming

Abstract

Bibliographical note

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

Other Access Options

Permanent Link

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Projects

ASDC_Sub: Futian Research Project: Identification of Noncoding RNA Driving Epigenetic Changes During Cellular Senescence

GRF: Unravelling the Molecular Mechanism of DNA Demethylation around CTCF Binding Sites in Mammalian Cells

Cite this