DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A
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Abstract
Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
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Increased expression of the H3K79 methyltransferase DOT1L during OIS promotes H3K79me2/3 occupancy at the IL1A locus, contributing to SASP gene expression.
“The increased expression of the H3K79 methyltransferase DOT1L during OIS promotes H3K79me2/3 occupancy at the IL1A locus, contributing to SASP gene expression [166].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [166]
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References 105 · Cited by 70
Research works printed but not linked: 1
- Chen, X., X. Liu, Y. Zhang, W. Huai, Q. Zhou, S. Xu, X. Chen, N. Li, and X. Cao. 2020. Methyltransferase Dot1l preferentially promotes innate IL-6 and IFN-β production by mediating H3K79me2/3 methylation in macrophages. Cell. Mol. Immunol. 17: 76– 84. 10.1038/s41423-018-0170-4 30275539 PMC6952432 · DOI
- Authors
- Leon, K. E., Buj, R., Lesko, E., Dahl, E. S., Chen, C.-W., Tangudu, N. K., Imamura-Kawasawa, Y., Kossenkov, A. V., Hobbs, R. P., & Aird, K. M.
- Affiliations
- Pennsylvania State University (US)
- University of Pittsburgh (US)
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA 4
- The Wistar Institute (US)
- Corresponding author
- Aird, Katherine M.
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2021-05-26
- Volume
- 220
- Issue
- 8
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC8160577
- OpenAlex
- W3165572879
- Cited by
- 70
- References
- 105
- Citations by year
- 2026: 14 · 2025: 8 · 2024: 15 · 2023: 11 · 2022: 15 · 2021: 7
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (F31CA250366, F31CA236372, R00CA194309, R37CA240625, P41 GM108569)
- W. W. Smith Charitable Trust
- Penn State Cancer Institute
- National Cancer Institute (P30 CA060553)
- NIH Office of the Director (S10OD025194)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DOT1L, senescence-associated secretory phenotype, oncogene-induced senescence, interleukin-1 alpha, H3K79 methylation, histone modifications, epigenetic regulation, STING, histone methyltransferase, tumor microenvironment
- MeSH terms
- STING Protein, Animals, Female, Fibroblasts, Histones, Humans, Membrane Proteins, Microscopy, Fluorescence, Papilloma, Phenotype, Histone-Lysine N-Methyltransferase, Skin Neoplasms, Tetradecanoylphorbol Acetate, 9,10-Dimethyl-1,2-benzanthracene, Cellular Senescence, DNA Methylation, CCAAT-Enhancer-Binding Protein-beta, Epigenesis, Genetic, Cell Proliferation, Mice, Interleukin-1alpha, Secretory Pathway, HEK293 Cells, Cell Cycle Checkpoints
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