Spatial Reorganization of Chromatin Architecture Shapes the Expression Phenotype of Therapy-Induced Senescent Cells

Area of Science:

• Genomics
• Cell Biology
• Epigenetics

Background:

• Cellular senescence, a state of irreversible cell cycle arrest, is linked to aging and involves significant chromatin remodeling.
• The role of three-dimensional (3D) genome organization in therapy-induced senescence (TIS) is not well understood.
• Understanding 3D genome dynamics in TIS is crucial for exploring therapeutic interventions and aging processes.

Purpose of the Study:

• To investigate the impact of TIS on the 3D genome architecture.
• To compare the effects of different TIS-inducing agents (ionizing radiation and bleomycin) on genome organization.
• To elucidate the relationship between 3D genome changes and gene expression, particularly for SASP genes.

Main Methods:

• Integrative multi-omics analysis including Hi-C, ATAC-seq, CUT&RUN, and RNA-seq.
• Induction of TIS in primary human fibroblasts using ionizing radiation (RAD) and bleomycin (BLEO).
• Computational analysis of chromatin structure, compartmentalization, TADs, and enhancer-promoter interactions.

Main Results:

• TIS induces global chromatin decompaction, weakened compartmentalization, and destabilized TADs.
• Distinct 3D regulatory programs are observed between RAD- and BLEO-induced senescence, affecting compartment strength and E-P loops.
• TIS reshapes the chromatin environment around SASP genes, with reduced interactions in adjacent regions facilitating transcriptional activation.

Conclusions:

• 3D genome remodeling during TIS is dynamic, plastic, and context-dependent.
• Spatial genome organization plays a significant role in regulating gene expression during TIS.
• This study provides novel insights into the interplay between senescence, 3D genome structure, and gene regulation.