Abstract
O-GlcNAc modification is a key cellular signal, but its role in regulating senescence-associated transcription remains poorly understood. Here, we apply a time-resolved chemical genomics strategy to map dynamic O-GlcNAc chromatin-associated proteins (OCPs) during oncogene-induced senescence (OIS) in primary human fibroblasts. Chromatin O-GlcNAc modification continues to accumulate, while 1,987 senescence-associated OCPs undergo dynamic shifts in genomic occupancy across diverse epigenetic chromatin states and display bimodal regulatory activities within the 3,466-gene senescence transcriptome. O-GlcNAc facilitates the formation of dual-function complexes: TF–SWI/SNF activates senescence-associated secretory phenotype (SASP) genes at promoters, whereas NuRD enforces th…
Abstract
O-GlcNAc modification is a key cellular signal, but its role in regulating senescence-associated transcription remains poorly understood. Here, we apply a time-resolved chemical genomics strategy to map dynamic O-GlcNAc chromatin-associated proteins (OCPs) during oncogene-induced senescence (OIS) in primary human fibroblasts. Chromatin O-GlcNAc modification continues to accumulate, while 1,987 senescence-associated OCPs undergo dynamic shifts in genomic occupancy across diverse epigenetic chromatin states and display bimodal regulatory activities within the 3,466-gene senescence transcriptome. O-GlcNAc facilitates the formation of dual-function complexes: TF–SWI/SNF activates senescence-associated secretory phenotype (SASP) genes at promoters, whereas NuRD enforces the repression of cell-cycle regulators at enhancers. Furthermore, we identify O-GlcNAc modified JUN and GATAD2A as key regulators of OIS phenotypes in both in vitro and in vivo models of senescence-driven tumorigenesis. These findings reveal dynamic regulation and chromatin organization principles of O-GlcNAc–related epigenetic factors, providing insights into cellular senescence and potential therapeutic strategies.
Data availability
The raw data of COGC-seq and ChIP-seq is available in the Gene Expression Omnibus database under the accession number GSE295087. The raw data of DNA methylation whole-genome bisulfite sequencing is available in the Gene Expression Omnibus database under the accession number GSE295084. The raw data of RNA-seq is available in the Gene Expression Omnibus database under the accession number GSE295083 [https://www.ncbi.xyz/geo/query/acc.cgi]. The raw mass spectral data in our study is available via iProX with identifier PXD063140. The raw data and files of MD simulation are available via Github [https://github.com/ATOMS-xjtlu/NuRD] and Zenodo [https://doi.org/10.5281/zenodo.17062795]. All additional data used to generate figures are provided in Supplementary Data 1–7. Source data are provided with this paper.
Code availability
The input code of MD simulation are available via Github [https://github.com/ATOMS-xjtlu/NuRD] and Zenodo [https://doi.org/10.5281/zenodo.17062795]. All additional code used to generate data are provided in methods.
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Acknowledgements
We thank Prof. Bo Cheng at Peking University for kindly providing 1,6-Pr2GalNAz. This study is supported by the National Natural Science Foundation of China (32171282, 32471331), Yubo Liu; Liaoning Province’s “Xingliao Talent Plan” Youth Top Talents (XLYC2203069), Yubo Liu; the Fundamental Research Funds for the Central Universities (DUT23YG114, DUT25YG244) and XJTLU Research Development Fund (RDF-23-01-100), S.W.
Author information
Author notes
These authors contributed equally: Nana Zhang, Ran Zhao, Xiaomin Zhong.
Authors and Affiliations
Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, China
Nana Zhang, Jianing Zhang, Wei Wang & Yubo Liu 1.
College of Life and Health Sciences, Northeastern University, Shenyang, China
Nana Zhang, Ran Zhao & Qian Dong 1.
Department of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
Nana Zhang, Kairan Yu, Lirui Han, Fanxu Meng, Huang Huang, Jianing Zhang & Yubo Liu 1.
Department of Oncology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
Xiaomin Zhong 1.
Instrumental Analysis Center, Dalian University of Technology, Dalian, China
Yajie Liu 1.
Jiangsu Province Higher Education Key Laboratory of Cell Therapy Nanoformulation (Construction), Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
Jiaxuan Wu & Sijin Wu 1.
Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong, China
Qiushi Chen & Xuechen Li 1.
Laboratory for Synthetic Chemistry and Chemical Biology Limited, Hong Kong, Science Park, Hong Kong, China
Qiushi Chen 1.
Shenzhen Salus BioMed Co., Ltd., Shenzhen, China
Qingbin Chen 1.
Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, China
Keren Zhang 1.
Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Yan Ren
Authors
- Nana Zhang
- Ran Zhao
- Xiaomin Zhong
- Qian Dong
- Yajie Liu
- Kairan Yu
- Lirui Han
- Fanxu Meng
- Jiaxuan Wu
- Qiushi Chen
- Xuechen Li
- Qingbin Chen
- Keren Zhang
- Huang Huang
- Jianing Zhang
- Sijin Wu
- Yan Ren
- Wei Wang
- Yubo Liu
Contributions
Yubo Liu and J.Z. conceived and designed the study. N.Z., Yajie Liu, K.Y., L.H., and F.M. performed experiments, and R.Z. and X.Z. supervised experiments. N.Z. and R.Z. performed bioinformatics analyses, and Yubo Liu and W.W. supervised bioinformatics analyses. Qingbin Chen performed the preparation of all sequencing samples. N.Z. and Y.R. performed LC-MS/MS and processed the data. Qiushi Chen, X.L., and K.Z. analyzed the mass spectrometry data. N.Z. and Q.D. acquired images using confocal microscopy; J.W. and S.W. performed molecular dynamics simulation; N.Z. obtained the next-generation sequencing data. Yubo Liu, N.Z., H.H., and J.Z. analyzed data. N.Z. and Yubo Liu contributed to and supervised the image analysis and prepared figures. All authors contributed to the experiments and supported data analyses. Yubo Liu, N.Z., S.W., W.W., and R.Y. wrote and revised the manuscript. All authors approved the manuscript.
Corresponding authors
Correspondence to Sijin Wu, Yan Ren, Wei Wang or Yubo Liu.
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Nature Communications thanks Stéphan Hardivillé, Anne-Sophie Vercoutter-Edouart, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Zhang, N., Zhao, R., Zhong, X. et al. Time-resolved multiomics profiling reveals chromatin O-GlcNAc modification promotes senescence-associated transcriptional program. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68143-z
Received: 03 June 2025
Accepted: 19 December 2025
Published: 08 January 2026
DOI: https://doi.org/10.1038/s41467-025-68143-z