Ligand-specific regulation of a binary enhancer code dictating cellular senescence.

Thomas Suter, Meyer J Friedman, Cagdas Tazearslan, Daria Merkurjev, Kenny Ohgi, Dario Meluzzi, Michael G Rosenfeld, Yousin Suh

Cellular and Molecular Medicine, Department of Medicine, University of California San Diego, La Jolla, CA 92093.Cellular and Molecular Medicine, Department of Medicine, University of California San Diego, La Jolla, CA 92093. · pubmed

Paper

Abstract

Cellular senescence, a major contributor to aging and age-related pathologies, is characterized by irreversible proliferative arrest and a disease-linked, proinflammatory profile known as the Senescence Associated Secretory Phenotype (SASP). A critical unanswered question is whether these properties are regulated by specific enhancer subsets, potentially licensing strategies that selectively block deleterious SASP components. Here, we identify two functionally distinct and independently regulated enhancer programs underlying senescence that are controlled by different TGF-β family ligands. Whereas Activin A stimulates recruitment of nuclear factor IA/C (NFIA/C) and SMAD2/3 transcription factors to an enhancer network that induces proliferation arrest, TGF-β2 promotes SMAD2/3-mediated suppression of a p65-dependent enhancer cohort driving the SASP. We have also uncovered reciprocal SMAD2/3-super-enhancer-regulated feedback loops that govern expression of the TGF-β2 (

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Research summary

The paper claims that distinct enhancer programs regulated by TGF-β family ligands control cellular senescence and the SASP. This research is relevant as it explores the underlying mechanisms of cellular senescence, which is a key contributor to aging and age-related diseases, potentially offering insights into strategies for mitigating these effects.

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