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

Area of Science:

• Epigenetics
• Molecular Biology
• Cellular Senescence

Background:

• O-GlcNAc modification is a crucial cellular signal with an unclear role in senescence-associated transcription.
• Understanding this role is vital for comprehending cellular aging and cancer development.

Purpose of the Study:

• To map dynamic O-GlcNAc chromatin-associated proteins (OCPs) during oncogene-induced senescence (OIS).
• To elucidate the regulatory mechanisms of O-GlcNAc in senescence-associated transcription and chromatin organization.

Main Methods:

• Employed a time-resolved chemical genomics strategy in primary human fibroblasts.
• Analyzed dynamic OCPs genomic occupancy and their association with epigenetic states during OIS.

Main Results:

• Observed continuous accumulation of chromatin O-GlcNAc modification during OIS.
• Identified 1,987 senescence-associated OCPs with dynamic genomic occupancy and bimodal regulatory roles in the senescence transcriptome.
• Discovered dual-function complexes (TF-SWI/SNF and NuRD) regulated by O-GlcNAc, influencing SASP genes and cell-cycle regulators.
• Identified O-GlcNAc-modified JUN and GATAD2A as key regulators of OIS phenotypes.

Conclusions:

• O-GlcNAc modification dynamically regulates chromatin organization and gene expression during cellular senescence.
• Findings provide insights into the epigenetic control of senescence and potential therapeutic targets for senescence-driven tumorigenesis.