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

• 成果类型: Article
• 署名作者: Suter, Thomas; Friedman, Meyer J.; Tazearslan, Cagdas; Merkurjev, Daria; Ohgi, Kenny; Meluzzi, Dario; Rosenfeld, Michael G.; Suh, Yousin
• 署名单位: University of California System; University of California San Diego; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Columbia University; NewYork-Presbyterian Hospital; NewYork-Presbyterian Hospital; Columbia University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13562
• DOI: 10.1073/pnas.2506321122
• 发表日期: 2025-06-17
• 关键词: one transcription factors; extends life-span; secretory phenotype; activin-a; cells; rapamycin; clearance; cancer; ORGANIZATION; landscapes

摘要

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-beta 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-beta 2 promotes SMAD2/3-mediated suppression of a p65-dependent enhancer cohort driving SASP. We have also uncovered reciprocal SMAD2/3-super-enhancer-regulated feedback loops that govern expression of the TGF-beta 2 (TGFB2) and Activin A (INHBA) transcription units, both of which are significantly up-regulated in replicative senescence. characteristic enhancer usage and transcriptional landscape of high-passage senescent cells are sensitive to rapamycin treatment, discontinuation of which results in robust but selective senescent enhancer activation and exacerbation of the SASP. Collectively, this study uncovers separable enhancer programs and their key constituent transcription factors that contribute to the canonical features of cellular senescence, potentially informing the development of SASP-targeted therapies.