Cellular senescence refers to an irreversible cell-cycle arrest program that cell permanently loses proliferative potential.It is regarded as an important mechanism against cancer and is closely related to tissue repair,organismal aging and age-related degenerative disease.Senescent cells are characterized with dramatic changes in cell morphology,gene expression pattern and epigenetic profiles.In this study,we used an interdisciplinary strategy by taking the advantage of computational predictions and systematically designed high throughput experiments to study the gene regulatory network of senescent cells.We applied a combination of Hi-C,ATAC-seq and transcriptome profiling to characterize gene regulation changes at different scale in proliferating,quiescent,senescent,and reverse senescent human fibroblast ceils.A high-throughput CRISPR-Cas9 library screening combined with deep-sequencing analysis was performed to identify key senescence regulatory genes.Our study revealed global changes of chromatin organization in senescent cells,and identified several new regulators participating this process.