# ERG phase separation attenuates cellular senescence

## TL;DR

The study finds that ERG protein phase separation in centenarians' cells may help delay aging by reducing senescence-related gene activity.

## Contribution

ERG phase separation is newly identified as a mechanism linking chromatin organization to cellular aging in centenarians.

## Key findings

- Centenarians' PBMCs show unique chromatin accessibility patterns.
- ERG phase separation reduces CDKN2A expression and senescence.
- ERG condensates alter chromatin organization and aging phenotypes.

## Abstract

Centenarians, individuals who reach extreme old age, provide a valuable model for understanding mechanisms associated with healthy aging. Using ATAC-seq and transcriptomic profiling of peripheral blood mononuclear cells from centenarians, we identified a distinct chromatin accessibility landscape linked to exceptional longevity. Integrative analysis highlighted the E-26 transformation-specific (ETS)-related transcription factor ERG as a longevity-associated regulator. Functional studies in human cells showed that ERG forms nuclear condensates through liquid-liquid phase separation, a property associated with altered chromatin organization and reduced expression of senescence-related genes, including CDKN2A. Consistent with these effects, ERG condensation was associated with attenuation of cellular senescence phenotypes. Together, these findings connect epigenomic features observed in centenarians with transcription factor biophysical properties and cellular aging control, highlighting phase separation as a regulatory layer that may contribute to cellular resilience during aging.

•Centenarian PBMCs exhibit distinct chromatin accessibility landscapes•ERG emerges as a transcription factor associated with human longevity•ERG phase separation represses CDKN2A transcription to limit cellular senescence

Centenarian PBMCs exhibit distinct chromatin accessibility landscapes

ERG emerges as a transcription factor associated with human longevity

ERG phase separation represses CDKN2A transcription to limit cellular senescence

Medical biochemistry; chromosome organization; biophysical chemistry