Integrative Profiling Identifies AP1 Transcription Factors as Pioneers and Conductors of the Senescence Cell Fate

Cellular senescence limits the proliferation of dysfunctional cells in response to diverse forms of cellular stress, playing essential roles in tumor suppression and tissue regeneration, while also contributing to age-related pathologies. Here, we used multidimensional profiling to define the temporal organization of the senescence transcriptional program, the transcription factor network topology that controls it and its underlying epigenome dynamics. We show that the senescence program is bookmarked epigenetically by AP1 transcription factors, which pioneer this cell fate transition by activating, licensing and decommissioning enhancers relevant to the senescence program, including the newly characterized classes of “de novo” and “remnant” enhancers. Functional studies informed by genome-wide analyses further underscored the instructive role of AP1-cJUN since its silencing partially resets the senescence clock to a past transcriptional state. Together, our findings identify dynamically regulated chromatin transitions critical for senescence commitment, thus defining promising targets for manipulating the senescence program for therapeutic benefit.