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Research Paper|Volume 15, Issue 19|pp 9984—10009

BMAL1 modulates senescence programming via AP-1

Sarah K. Jachim1,2, Jian Zhong3, Tamas Ordog4,5, Jeong-Heon Lee3,5, Aditya V. Bhagwate6, Nagaswaroop Kengunte Nagaraj6, Jennifer J. Westendorf7, João F. Passos2,4, Aleksey V. Matveyenko4,8, Nathan K. LeBrasseur2,9
  • 1Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
  • 2Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
  • 3Epigenomics Development Laboratory, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
  • 4Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
  • 5Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA
  • 6Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
  • 7Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
  • 8Department of Medicine, Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
  • 9Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA
Received: July 30, 2023Accepted: September 18, 2023Published: October 10, 2023
https://doi.org/10.18632/aging.205112

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.