Senescence-Associated Chromatin Rewiring Promotes Inflammation and Transposable Element Activation

Area of Science:

• Genomics
• Epigenetics
• Cell Biology

Background:

• Cellular senescence, a state of irreversible cell cycle arrest, is linked to aging and disease via the senescence-associated secretory phenotype (SASP).
• While transcriptional and epigenetic factors are known drivers of senescence, the role of higher-order genome organization is less understood.

Purpose of the Study:

• To investigate the contribution of 3D genome architecture to cellular senescence.
• To analyze high-resolution chromatin organization in proliferating, quiescent, and senescent human fibroblasts.

Main Methods:

• Generation of highest-resolution Hi-C maps (~3 kb) for human fibroblasts in different cellular states.
• Comprehensive analysis of 3D genome architecture, including compartments, subcompartments, and chromatin loops.
• Correlation of structural changes with DNA methylation, gene expression, and retrotransposon activity.

Main Results:

• Widespread remodeling of chromatin architecture in senescent cells, with compartment switching and increased chromatin loops.
• Altered 3D genome structure correlates with DNA hypomethylation, SASP gene expression, and activation of LINE-1 retrotransposons.
• Distinct chromatin configurations differentiate senescence from quiescence, despite similar gene repression.

Conclusions:

• 3D genome architecture plays a crucial role in establishing and maintaining the senescent state.
• Changes in chromatin structure facilitate the expression of SASP and inflammatory pathways.
• Quiescent cells share inflammatory gene expression with senescent cells, highlighting the importance of experimental design.