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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月8日

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  • 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

摘要

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.