4D Genome Rewiring during Oncogene-Induced and Replicative Senescence

Area of Science:

• Cell Biology
• Genomics
• Epigenetics

Background:

• Cellular senescence, a state of irreversible growth arrest, involves significant changes in genome organization.
• Understanding the differences between replicative senescence (RS) and oncogene-induced senescence (OIS) is crucial for comprehending aging and cancer.
• The 3D genome architecture plays a role in regulating gene expression during senescence.

Purpose of the Study:

• To investigate the 3D genome reorganization during replicative senescence (RS) and oncogene-induced senescence (OIS).
• To identify key molecular players and structural changes driving senescence-associated heterochromatin formation and gene expression.
• To differentiate the 3D genome conformations between RS and OIS.

Main Methods:

• Generation of genome-wide chromatin interaction maps, epigenome profiling, replication-timing analysis, whole-genome bisulfite sequencing, and gene expression analysis.
• Identification and characterization of senescence-associated heterochromatin domains (SAHDs) and senescence-associated heterochromatin foci (SAHFs).
• Functional studies involving DNMT1 depletion to assess its role in SAHF formation and 3D genome conformation.

Main Results:

• Senescence-associated heterochromatin domains (SAHDs) were identified in both RS and OIS.
• Senescence-associated heterochromatin foci (SAHFs) formation was specific to OIS, driven by differential intra- versus inter-SAHD interactions.
• OIS-specific SAHFs promote the expression of nearby active genes by altering spatial proximity.
• DNMT1 was identified as a key factor inducing SAHFs via HMGA2, and its depletion reverted OIS cells to an RS-like 3D genome conformation.

Conclusions:

• Multi-omics and imaging approaches reveal distinct 3D genome organizations in RS and OIS.
• SAHF formation is a hallmark of OIS, influencing gene expression through spatial genome reorganization.
• DNMT1 and HMGA2 are critical determinants of acute senescence and SAHF formation in OIS.