Research Paper Volume 15, Issue 19 pp 9984—10009
BMAL1 modulates senescence programming via AP-1
- 1 Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
- 2 Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
- 3 Epigenomics Development Laboratory, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
- 4 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- 5 Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA
- 6 Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
- 7 Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- 8 Department of Medicine, Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
- 9 Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA
Received: July 30, 2023 Accepted: September 18, 2023 Published: October 10, 2023
https://doi.org/10.18632/aging.205112How to Cite
Copyright: © 2023 Jachim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Cellular senescence and circadian dysregulation are biological hallmarks of aging. Whether they are coordinately regulated has not been thoroughly studied. We hypothesize that BMAL1, a pioneer transcription factor and master regulator of the molecular circadian clock, plays a role in the senescence program. Here, we demonstrate BMAL1 is significantly upregulated in senescent cells and has altered rhythmicity compared to non-senescent cells. Through BMAL1-ChIP-seq, we show that BMAL1 is uniquely localized to genomic motifs associated with AP-1 in senescent cells. Integration of BMAL1-ChIP-seq data with RNA-seq data revealed that BMAL1 presence at AP-1 motifs is associated with active transcription. Finally, we showed that BMAL1 contributes to AP-1 transcriptional control of key features of the senescence program, including altered regulation of cell survival pathways, and confers resistance to drug-induced apoptosis. Overall, these results highlight a previously unappreciated role of the core circadian clock component BMAL1 on the molecular phenotype of senescent cells.