DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

Leon, Kelly E.; Buj, Raquel; Lesko, Elizabeth; Dahl, Erika S.; Chen, Chi‐Wei; Tangudu, Naveen K.; Imamura‐Kawasawa, Yuka; Kossenkov, Andrew V.; Hobbs, Ryan P.; Aird, Katherine M.

doi:10.1083/jcb.202008101

Cited by 44 publications

(27 citation statements)

References 97 publications

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“…The importance of these and other SASP factors has been verified in multiple biological contexts. [56][57][58][59][60][61][62][63] Interestingly, the control of the SASP itself by RELA/p65, which we detected in two sequencing datasets of aging women, has recently been experimentally verified in U2OS osteosarcoma cells. 64 Transcriptome-wide state-of-the-art technologies such as scRNA-seq will help shape our understanding of not just aging, but also therapeutics that potentially target fundamental mechanisms of aging, such as senolytics.…”

Section: Discussionmentioning

confidence: 54%

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A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

Saul

Kosinsky

Atkinson

et al. 2021

Preprint

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Although cellular senescence is increasingly recognized as driving multiple age-related co-morbidities through the senescence-associated secretory phenotype (SASP), in vivo senescent cell identification, particularly in bulk or single cell RNA-sequencing (scRNA-seq) data remains challenging. Here, we generated a novel gene set (SenMayo) and first validated its enrichment in bone biopsies from two aged human cohorts. SenMayo also identified senescent cells in aged murine brain tissue, demonstrating applicability across tissues and species. For direct validation, we demonstrated significant reductions in SenMayo in bone following genetic clearance of senescent cells in mice, with similar findings in adipose tissue from humans in a pilot study of pharmacological senescent cell clearance. In direct comparisons, SenMayo outperformed all six existing senescence/SASP gene sets in identifying senescent cells across tissues and in demonstrating responses to senescent cell clearance. We next used SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from publicly available human and murine bone marrow/bone scRNA-seq data and identified monocytic and osteolineage cells, respectively, as showing the highest levels of senescence/SASP genes. Using pseudotime and cellular communication patterns, we found senescent hematopoietic and mesenchymal cells communicated with other cells through common pathways, including the Macrophage Migration Inhibitory Factor (MIF) pathway, which has been implicated not only in inflammation but also in immune evasion, an important property of senescent cells. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Moreover, using this senescence panel, we were able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways associated with these cells, which may be particularly useful for evolving efforts to map senescent cells (e.g., SenNet). In addition, SenMayo represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

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Section: Discussionmentioning

confidence: 54%

“…The importance of these and other SASP factors has been verified in multiple biological contexts. 56–63 Interestingly, the control of the SASP itself by RELA/p65, which we detected in two sequencing datasets of aging women, has recently been experimentally verified in U2OS osteosarcoma cells. 64…”

Section: Discussionmentioning

confidence: 56%

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

Saul

Kosinsky

Atkinson

et al. 2021

Preprint

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“…These observations indicated that DOT1L regulates SASP through a DDR-independent mechanism, and that DOT1L expression is required for the SASP but is dispensable for other senescent cell phenotypes. Overall, this study suggested DOT1L as an epigenetic regulator of SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest (62).…”

Section: Stress Reprograms Cells To Sasp Locking In and Leading To The Long-term Effects Of Saspmentioning

confidence: 67%

Senescence-Associated Secretory Phenotype as a Hinge Between Cardiovascular Diseases and Cancer

Banerjee

Kotla

Velatooru

et al. 2021

Front. Cardiovasc. Med.

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Overlapping risks for cancer and cardiovascular diseases (CVD), the two leading causes of mortality worldwide, suggest a shared biology between these diseases. The role of senescence in the development of cancer and CVD has been established. However, its role as the intersection between these diseases remains unclear. Senescence was originally characterized by an irreversible cell cycle arrest after a high number of divisions, namely replicative senescence (RS). However, it is becoming clear that senescence can also be instigated by cellular stress, so-called stress-induced premature senescence (SIPS). Telomere shortening is a hallmark of RS. The contribution of telomere DNA damage and subsequent DNA damage response/repair to SIPS has also been suggested. Although cellular senescence can mediate cell cycle arrest, senescent cells can also remain metabolically active and secrete cytokines, chemokines, growth factors, and reactive oxygen species (ROS), so-called senescence-associated secretory phenotype (SASP). The involvement of SASP in both cancer and CVD has been established. In patients with cancer or CVD, SASP is induced by various stressors including cancer treatments, pro-inflammatory cytokines, and ROS. Therefore, SASP can be the intersection between cancer and CVD. Importantly, the conventional concept of senescence as the mediator of cell cycle arrest has been challenged, as it was recently reported that chemotherapy-induced senescence can reprogram senescent cancer cells to acquire “stemness” (SAS: senescence-associated stemness). SAS allows senescent cancer cells to escape cell cycle arrest with strongly enhanced clonogenic growth capacity. SAS supports senescent cells to promote both cancer and CVD, particularly in highly stressful conditions such as cancer treatments, myocardial infarction, and heart failure. As therapeutic advances have increased overlapping risk factors for cancer and CVD, to further understand their interaction may provide better prevention, earlier detection, and safer treatment. Thus, it is critical to study the mechanisms by which these senescence pathways (SAS/SASP) are induced and regulated in both cancer and CVD.

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“…This results in a decrease in histone H3 lysine 9 dimethylation (H3K9me2; a repressive chromatin modification) at the promoters of SASP genes that subsequently enhances IL-6 and IL-8 induction [ 165 ]. The increased expression of the H3K79 methyltransferase DOT1L during OIS promotes H3K79me2/3 occupancy at the IL1A locus, contributing to SASP gene expression [ 166 ]. SASP gene expression is also directly regulated by the histone variant macroH2A1 that accumulates during senescence [ 167 ].…”

Section: Transcriptional and Post-transcriptional Control Of Senescencementioning

confidence: 99%

Mechanisms and Regulation of Cellular Senescence

Roger

Tomas

Gire

2021

IJMS

179

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Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.

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DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

Cited by 44 publications

References 97 publications

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

Senescence-Associated Secretory Phenotype as a Hinge Between Cardiovascular Diseases and Cancer

Mechanisms and Regulation of Cellular Senescence

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