Abstract 2448 Functions of Small Maf Proteins in Senescence

Epigenetic alteration is a major driver of cellular senescence and cancer, and the reversibility of epigenetic modifications provides a highly optimistic avenue for anti-senescence and anti-cancer therapy development. Thus, a comprehensive understanding of specific epigenetic changes governing cellular senescence is crucial for devising targeted therapeutic strategies to improve patient outcomes. Gene expression programs are regulated by enhancers, which reside at great distances from their target genes and act in a context-specific manner. Senescence is accompanied by extensive three-dimensional (3D) genome reorganization, and our prior investigations identified numerous dysregulated hyper-connected enhancer clusters linked to potential dysregulated genes in senescent cells. We found MafK, a member of the small Maf proteins, mediates 3D enhancer landscape changes during senescence, corresponding to distinct gene expression programs. Furthermore, depletion of MafK does not affect the cell cycle arrest but significantly alleviates senescence-associated phenotypes, including the expression of SASP genes and the accumulation of β-galactosidase in various senescent cell types. These findings underscore the significance of transcription factor-mediated genome organization in gene regulation during senescence, and positions MafK as a promising candidate for senomorphic treatment strategies targeting aging and cancer. We express our sincere gratitude to the National Institute on Aging (NIA) and Cancer Prevention and Research Institute of Texas (CPRIT) for their funding support, which has been instrumental in advancing our research endeavors.