HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types

Area of Science:

• Cell Biology
• Genomics
• Molecular Biology

Background:

• Cellular senescence is a complex process leading to heterogeneous cell populations.
• Early molecular events driving senescence entry remain poorly understood.
• The role of three-dimensional (3D) genome organization in senescence initiation is largely unexplored.

Purpose of the Study:

• To investigate the hypothesis that early disruption of 3D genome organization triggers senescence entry.
• To identify key molecular events and proteins involved in the initial stages of senescence.
• To elucidate the relationship between genome architecture and the senescent phenotype.

Main Methods:

• Combined Hi-C, single-cell and population transcriptomics, and imaging techniques.
• Utilized in silico modeling across three distinct cell types undergoing senescence.
• Investigated the role of HMGB2 protein and CTCF clustering in genome organization.

Main Results:

• Genes regulating DNA conformation maintenance are suppressed during senescence entry.
• Nuclear depletion of HMGB2 protein and spatial clustering of CTCF occur early in senescence.
• HMGB2 knockdown induces CTCF clustering and loop reshuffling, while HMGB2 overexpression rescues these changes.

Conclusions:

• Early disruption of 3D genome organization, mediated by HMGB2, is a key event in senescence initiation.
• HMGB2 protein depletion and subsequent CTCF clustering are critical for initiating the senescent program.
• Genomic reorganization driven by HMGB2 acts as a primer for cellular senescence.