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

Area of Science:

• Molecular Biology
• Cell Biology
• Aging Research

Background:

• Cellular senescence is a key driver of aging and age-related diseases.
• It involves irreversible cell cycle arrest and the Senescence Associated Secretory Phenotype (SASP), a pro-inflammatory profile.
• Understanding the regulation of these processes is crucial for developing targeted therapies.

Purpose of the Study:

• To identify specific enhancer subsets regulating cellular senescence and the SASP.
• To investigate the roles of TGF-β family ligands in controlling these enhancer programs.
• To explore potential therapeutic strategies for modulating senescence-associated inflammation.

Main Methods:

• Identification and characterization of distinct enhancer programs in senescent cells.
• Analysis of transcription factor recruitment (NFIA/C, SMAD2/3, p65) to regulatory elements.
• Investigation of TGF-β2 and Activin A signaling pathways.
• Assessment of rapamycin's effects on senescence and SASP.
• Analysis of gene expression for TGF-β2 and Activin A.

Main Results:

• Two independent enhancer programs control senescence proliferation arrest and SASP.
• Activin A and TGF-β2, via distinct transcription factor networks, differentially regulate these programs.
• Reciprocal feedback loops involving SMAD2/3-super-enhancers control TGF-β2 and Activin A expression.
• Rapamycin treatment affects enhancer usage, and its discontinuation exacerbates the SASP.

Conclusions:

• Separable enhancer programs and their associated transcription factors drive key features of cellular senescence.
• These findings provide insights into the molecular mechanisms underlying aging and SASP.
• The study offers potential targets for developing therapies to combat age-related pathologies by selectively modulating the SASP.