Dynamic Multi-omics Profiling Unveils Bimodal Epigenetic Roles of Chromatin O-GlcNAc modification in Premature Senescence Program [RNA-seq]

Cellular senescence, a recognized instigator of tumorigenesis and age-associated disorders, can be precipitated by characteristic alterations in gene expression profiles. However, the underlying mechanisms that precise orchestrate the expression of senescence-related genes are still elusive. Here, we employed a time-series approach using a chemical genomics multi-omics strategy to panoramically investigate the role of O-GlcNAc chromatin-associated proteins (OCPs) throughout the process of oncogene-induced senescence (OIS) in human primary fibroblasts. The progression of OIS is associated with the dynamic accumulation of chromatin O-GlcNAc modification, which facilitates cells commitment to senescence. Through the integration of dynamic analyses of transcriptome and epigenome profiles, we can demonstrate that OCPs experience genomic occupation shifts across diverse epigenetic chromatin states, and display bimodal sequential regulatory activity within the senescence transcriptome. Mechanistically, O-GlcNAc aids in the formation of bimodal epigenetic regulatory complexes (TF-SWI/SNF and NuRD), which dictate the gene expression patterns related to both the senescence-associated secretory phenotype (SASP) and cell cycle arrest. Additionally, we pinpointed O-GlcNAc JUN and GATAD2A as key regulators affecting the phenotypes of OIS in both in vitro and in vivo models of senescence and tumorigenesis. Our findings on the dynamic behavior and chromatin organization principles of O-GlcNAc epigenetic factors provide insights into the senescence process and enable potential therapeutic manipulation of the senescence phenotype.