Time-resolved multiomics profiling reveals chromatin O-GlcNAc modification promotes senescence-associated transcriptional program

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

doi:10.1038/s41467-025-68143-z

Time-resolved multiomics profiling reveals chromatin O-GlcNAc modification promotes senescence-associated transcriptional program

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^*

^*Corresponding author for this work

AoPHA Faculty

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Nature Communications
DOIs	https://doi.org/10.1038/s41467-025-68143-z
Publication status	Published - 2026

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10.1038/s41467-025-68143-z

Cite this

Zhang, N., Zhao, R., Zhong, X., Dong, Q., Liu, Y., Yu, K., Han, L., Meng, F., Wu, J., Chen, Q., Li, X., Chen, Q., Zhang, K., Huang, H., Zhang, J., Wu, S., Ren, Y., Wang, W., & Liu, Y. (2026). Time-resolved multiomics profiling reveals chromatin O-GlcNAc modification promotes senescence-associated transcriptional program. Nature Communications. https://doi.org/10.1038/s41467-025-68143-z

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title = "Time-resolved multiomics profiling reveals chromatin O-GlcNAc modification promotes senescence-associated transcriptional program",

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.",

author = "Nana Zhang and Ran Zhao and Xiaomin Zhong and Qian Dong and Yajie Liu and Kairan Yu and Lirui Han and Fanxu Meng and Jiaxuan Wu and Qiushi Chen and Xuechen Li and Qingbin Chen and Keren Zhang and Huang Huang and Jianing Zhang and Sijin Wu and Yan Ren and Wei Wang and Yubo Liu",

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doi = "10.1038/s41467-025-68143-z",

language = "English",

journal = "Nature Communications",

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T1 - Time-resolved multiomics profiling reveals chromatin O-GlcNAc modification promotes senescence-associated transcriptional program

AU - Zhang, Nana

AU - Zhao, Ran

AU - Zhong, Xiaomin

AU - Dong, Qian

AU - Liu, Yajie

AU - Yu, Kairan

AU - Han, Lirui

AU - Meng, Fanxu

AU - Wu, Jiaxuan

AU - Chen, Qiushi

AU - Li, Xuechen

AU - Chen, Qingbin

AU - Zhang, Keren

AU - Huang, Huang

AU - Zhang, Jianing

AU - Wu, Sijin

AU - Ren, Yan

AU - Wang, Wei

AU - Liu, Yubo

PY - 2026

Y1 - 2026

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-025-68143-z

DO - 10.1038/s41467-025-68143-z

M3 - Article

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -