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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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 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

(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 -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