Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression

Contrepois, Kévin; Coudereau, Clément; Benayoun, Bérénice A.; Schuler, Nadine; Roux, Pierre-François; Bischof, Oliver; Courbeyrette, Régis; Carvalho, Cyril; Thuret, Jean‐Yves; Ma, Zhihai; Derbois, Céline; Nevers, Marie‐Claire; Volland, Hervé; Redon, Christophe E.; Bonner, William M.; Deleuze, Jean‐François; Wiel, Clotilde; Bernard, David; Snyder, M; Rübe, Claudia E.; Olaso, Robert; Fenaille, François; Mann, Carl

doi:10.1038/ncomms14995

Cited by 159 publications

(142 citation statements)

References 53 publications

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“…By using different pharmacological inhibitors, our results suggest a dichotomic regulation of expression of p16 INK4a , a growth arrest-related characteristics of senescence, and VEGFα production by CSE-induced senescent CCR6 + Th17 cells, as already reported for the SASP of other cell types 32,33 . In support of this is the selective inhibition of CSE-induced production of VEGFα by NAC pretreatment, in comparison with the antimycin A -sensitivity of CSE-stimulated p16 INK4a expression.…”

Section: Discussionsupporting

confidence: 80%

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion

Baskara

Kerbrat

Dagouassat

et al. 2020

Sci Rep

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Chronic exposure to environmental pollutants is often associated with systemic inflammation. As such, cigarette smoking contributes to inflammation and lung diseases by inducing senescence of pulmonary cells such as pneumocytes, fibroblasts, and endothelial cells. Yet, how smoking worsens evolution of chronic inflammatory disorders associated with Th17 lymphocytes, such as rheumatoid arthritis, psoriasis, Crohn's disease, and multiple sclerosis, is largely unknown. Results from human studies show an increase in inflammatory CD4 + Th17 lymphocytes at blood-and pulmonary level in smokers. The aim of the study was to evaluate the sensitivity of CD4 + Th17 lymphocytes to cigarette smoke-induced senescence. Mucosa-homing CCR6 + Th17-were compared to CCR6 neg -and regulatory T peripheral lymphocytes after exposure to cigarette smoke extract (CSE). Senescence sensitivity of CSE-exposed cells was assessed by determination of various senescence biomarkers (β-galactosidase activity, p16 Ink4a -and p21 expression) and cytokines production. CCR6 + Th17 cells showed a higher sensitivity to CSE-induced senescence compared to controls, which is associated to oxidative stress and higher VeGfα secretion. Pharmacological targeting of ROS-and ERK1/2 signalling pathways prevented CSEinduced senescence of CCR6 + Th17 lymphocytes as well as VEGFα secretion. Altogether, these results identify mechanisms by which pro-oxidant environmental pollutants contribute to pro-angiogenic and pathogenic CCR6 + Th17 cells, therefore potential targets for therapeutic purposes.open Scientific RepoRtS | (2020) 10:6488 | https://doi.Statistical analysis. The sample sizes were dependent on the experimental question and are shown in the related figures. 32 individual healthy donors were studied for all experiments shown in this manuscript. At least, 4individual healthy donors were used for the study of each marker of senescence. Each donor was used to test two different biomarkers at least, depending on the yield of T cells sorting. Statistical analysis tests were performed using Prism version 5.04 (GraphPad, La Jolla, CA, USA) and data are represented as mean standard error of the mean (SEM). As the gaussian distribution of the different biomarkers could not be checked, non-parametric tests were used to address their statistical relevance. The Mann-Whitney test was used to compare the means of two groups of ordinal (non-parametric) data, and the Kruskal-Wallis test (non-parametric test) was used to compare between the 3 groups.

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Section: Discussionsupporting

confidence: 80%

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion

Baskara

Kerbrat

Dagouassat

et al. 2020

Sci Rep

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“…2c). By contrast, we observed that chronic irradiation led to enhanced levels of histone H2A.J, a histone variant recently shown to accumulate specifically in senescent cells 33 . To extend our analyses further, we employed a quantitative protein analysis approach -stable isotope labelling of amino acids in cell culture (SILAC) followed by quantitative mass spectrometry analyses -to measure and compare histone levels in irradiated and non-irradiated cells.…”

Section: Scientific Reports |contrasting

confidence: 72%

Chronic irradiation of human cells reduces histone levels and deregulates gene expression

Lowe

Herzog

Mosler

et al. 2020

Sci Rep

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Over the past decades, there have been huge advances in understanding cellular responses to ionising radiation (IR) and DNA damage. These studies, however, were mostly executed with cell lines and mice using single or multiple acute doses of radiation. Hence, relatively little is known about how continuous exposure to low dose ionising radiation affects normal cells and organisms, even though our cells are constantly exposed to low levels of radiation. We addressed this issue by examining the consequences of exposing human primary cells to continuous ionising γ-radiation delivered at 6-20 mGy/h. Although these dose rates are estimated to inflict fewer than a single DNA double-strand break (DSB) per hour per cell, they still caused dose-dependent reductions in cell proliferation and increased cellular senescence. We concomitantly observed histone protein levels to reduce by up to 40%, which in contrast to previous observations, was not mainly due to protein degradation but instead correlated with reduced histone gene expression. Histone reductions were accompanied by enlarged nuclear size paralleled by an increase in global transcription, including that of pro-inflammatory genes. Thus, chronic irradiation, even at low dose-rates, can induce cell senescence and alter gene expression via a hitherto uncharacterised epigenetic route. these features of chronic radiation represent a new aspect of radiation biology.www.nature.com/scientificreports www.nature.com/scientificreports/ based on the widely assumed model that there is a linear relationship between dose and risk. It is impossible to ascertain which of these is correct because the number of reported studies is low, and they come from a wide range of experimental sources, which do not lend themselves to direct comparison. Furthermore, conceptual extrapolation of our understanding of DNA damage signalling induced by high and acute doses of radiation may be incorrect, as DNA damage inflicted by low-dose chronic radiation is very different. It is unclear whether there is a threshold of DNA damage that must be breached for cells to respond, and whether continuous and consecutive DNA damage will be tolerated or ignored by the cell. As it has been suggested that persistent DNA-damage signalling can drive cells into senescence 14 , it may be that repeated, albeit low levels of, DNA damage from chronic radiation prevents complete diminution of DNA damage signals below a theoretical minimum level or interval, thereby causing cells to initiate and progress into a senescent state. There is increasing appreciation of the importance of these issues because of the growing use of medical procedures such as computed tomography (CT), which can give more than an average year's total radiation dose in a single scan 15 . However, the experimental model, endpoint and risk measure will always be critical to this assessment.Outside the field of radiobiology, attention is increasingly drawn to the importance of non-genetic changes in cancer and non-cancer pathologies. These changes inclu...

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“…The author proposed that the appearance of markers of senescence does not mean that the cells are truly senescent, but are exhibiting an adaptive stress response (Webster et al, 2015). 6 | CELLULAR SENESCENCE IS ASSOCIATED WITH AGING-ASSOCIATED DISEASES 6.1 | Cellular senescence is associated with chronic inflammation Senescent cells can normally be recognized and cleared by the immune system (Sagiv & Krizhanovsky, 2013 required for the immune system to recognize senescent cells, which contributes to chronic inflammation and aging-associated diseases (Contrepois et al, 2017). Interestingly, p53 signaling seems to decrease with age, whereas NF-κB signaling is increased.…”

Section: Wnt Signalingmentioning

confidence: 99%

Cellular senescence: Molecular mechanisms and pathogenicity

Wei

2018

Journal Cellular Physiology

161

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Cellular senescence is the arrest of normal cell division. Oncogenic genes and oxidative stress, which cause genomic DNA damage and generation of reactive oxygen species, lead to cellular senescence. The senescence-associated secretory phenotype is a distinct feature of senescence. Senescence is normally involved in the embryonic development. Senescent cells can communicate with immune cells to invoke an immune response. Senescence emerges during the aging process in several tissues and organs. In fact, increasing evidence shows that cellular senescence is implicated in aging-related diseases, such as nonalcoholic fatty liver disease, obesity and diabetes, pulmonary hypertension, and tumorigenesis. Cellular senescence can also be induced by microbial infection. During cellular senescence, several signaling pathways, including those of p53, nuclear factor-κB (NF-κB), mammalian target of rapamycin, and transforming growth factor-beta, play important roles. Accumulation of senescent cells can trigger chronic inflammation, which may contribute to the pathological changes in the elderly. Given the variety of deleterious effects caused by cellular senescence in humans, strategies have been proposed to control senescence. In this review, we will focus on recent studies to provide a brief introduction to cellular senescence, including associated signaling pathways and pathology.

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Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression

Cited by 159 publications

References 53 publications

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion

Chronic irradiation of human cells reduces histone levels and deregulates gene expression

Cellular senescence: Molecular mechanisms and pathogenicity

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