The shape and packaging of nuclear DNA is actively controlled by the cell via decoration of the DNA and supporting structures with additional molecular motifs, such as methyl groups. At any given time much of the genome is tightly spooled into regions known as heterochromatin that are inaccessible to the machinery of gene expression that surrounds nuclear DNA, constantly interacting with it. The structure of nuclear DNA determines gene expression, which regions are unspooled and accessible to translation machinery for the production of RNA from gene sequences versus which regions are spooled and the genes there silenced.
Here researchers examine immune cells from centenarian blood samples and note a distinct pattern of structure in their DNA. Further investigation points to one specific transcription factor, ERG, that appears to reduce cellular senescence, and thus might be theorized to improve immune function in the aged tissue environment. There are no doubt many other specific differences in activity that might be investigated more deeply, however. Transcription factors alter DNA structure and other aspects of gene expression for many genes, thousands in some cases. They are thus interesting points of potential intervention in the behavior of the cell, a greater centralization of regulatory control over function than most genes.
ERG phase separation attenuates cellular senescence
Our study defines a distinct chromatin accessibility signature in perihipheral blood mononuclear cells of centenarians, characterized by a global increase in chromatin openness across multiple immune subsets. Notably, this increase does not reflect accelerated senescence as aging usually along with increase chromatin accessibility, but rather suggests a unique chromatin configuration associated with exceptional longevity. In particular, B cells from centenarians display enhanced accessibility at promoter and enhancer regions that typically close with age, while closing peaks are enriched in quiescent loci that generally open during aging. These findings highlight that centenarians maintain an atypical epigenetic state, potentially supporting immune resilience and genomic stability in extreme old age.
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 cellular 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.
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