bioRxiv preprint doi: https://doi.org/10.1101/633594; this version posted May 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
AP-1 Imprints a Reversible Transcriptional Program of Senescent Cells
Ricardo Iván Martínez-Zamudio1,5,8, Pierre-François Roux1,5, José Américo N L F de
Freitas1,4, Lucas Robinson1,4, Gregory Doré1, Bin Sun6,7, Jesús Gil6,7, Utz Herbig8 and
Oliver Bischof1,2,3,9*
1 Institut Pasteur, Laboratory of Nuclear Organization and Oncogenesis, Department of
Cell Biology and Infection, 75015 Paris, France
2 INSERM, U993, 75015 Paris, France
3 Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Paris, France
4 Université de Paris, Sorbonne Paris Cité, Paris, France
5 These authors contributed equally to this work
6 MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN,
UK.
7 Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du
Cane Road, London W12 0NN, UK.
8 Department of Microbiology, Biochemistry & Molecular Genetics, Rutgers Biomedical &
Health Sciences, Rutgers University, 205 South Orange Avenue, Newark, NJ 07103,
USA
9 Lead contact
*Correspondence: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/633594; this version posted May 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
SUMMARY
Senescent cells play important physiological- and pathophysiological roles in tumor
suppression, tissue regeneration, and aging. While select genetic and epigenetic
elements crucial for senescence induction were identified, the dynamics, underlying
epigenetic mechanisms, and regulatory networks defining senescence competence,
induction and maintenance remain poorly understood, precluding a deliberate
therapeutic manipulation of these dynamic processes. Here, we show, using dynamic
analyses of transcriptome and epigenome profiles, that the epigenetic state of
enhancers predetermines their sequential activation during senescence. We
demonstrate that activator protein 1 (AP-1) ‘imprints’ the senescence enhancer
landscape effectively regulating transcriptional activities pertinent to the timely execution
of the senescence program. We define and validate a hierarchical transcription factor
(TF) network model and demonstrate its effectiveness for the design of senescence
reprogramming experiments. Together, our findings define the dynamic nature and
organizational principles of gene-regulatory elements driving the senescence program
and reveal promising inroads for therapeutic manipulation of senescent cells.
bioRxiv preprint doi: https://doi.org/10.1101/633594; this version posted May 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
INTRODUCTION
Cellular senescence plays beneficial roles during embryonic development, wound
healing, and tumor suppression. Paradoxically, it is also considered a significant
contributor to aging and age-related diseases including cancer and degenerative
pathologies1. As such, research on therapeutic strategies exploiting senescence
targeting (e.g., senolytics, senomorphics or pro-senescence cancer therapies) to
improve healthspan has gained enormous momentum in recent years2.
Cellular senescence is a cell fate that stably arrests proliferation of damaged and
dysfunctional cells as a