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A hierarchical TF network defines the senescence transcriptional programme Heatmap describing the association of individual TFs (row) with TF lexicons (columns). Four boxed out insets provide detailed information on the TF composition of lexicons. A comprehensive, high-resolution and interactive heatmap is shown in Supplementary Data 1. The right curve shows the total number of binding sites for each TF. The top curve shows the total number of regions for each regulatory module. The bottom curve shows the average proportion of AP-1-binding sites inside each regulatory module.
Source publication
Senescent cells affect many physiological and pathophysiological processes. While select genetic and epigenetic elements for senescence induction have been identified, the dynamics, epigenetic mechanisms and regulatory networks defining senes- cence competence, induction and maintenance remain poorly understood, precluding the deliberate therapeuti...
Citations
... Furthermore, our findings also uncovered that JUNB regulation of SASP transcription could be through facilitating enhancer-promoter looping formation. This is in line with an earlier report demonstrating AP-1 TFs pioneer the senescence enhancer landscape and drive the transcriptional program in human lung fibroblasts undergoing oncogene-induced senescence [52]. Notably, when extending our study to IMR-90 cells induced to senescence by ETO or replication, we also validated the positive role of JUNB in regulating SASP transcription potentially via facilitating E-P looping. ...
Cellular senescence is recognized as a hallmark of organismal aging but how it drives aging particularly in human tissues is not fully understood, partly due to the complex heterogeneous nature of senescence. Here in this study, we leverage single-nucleus multiomics to profile senescence in mononucleated cells of human skeletal muscle and provide the first senescence atlas. We demonstrate the intra- and inter-populational transcriptomic and epigenomic heterogeneity and dynamics of senescence in the cells. We also identify commonalities and variations in senescence-associated secretory phenotypes (SASPs) among the cells and elucidate the function of SASPs in mediating cellular interactions and niche deregulation. Furthermore, we identify targetable SASP factors and demonstrate the possibility of using Maraviroc as a senotherapeutics for treating age-associated sarcopenia in muscle. Lastly, we also define transcription factors that govern senescence state and SASP induction in aging muscle and elucidate the key function and the underlying mechanism of JUNB in regulating SASP activation in senescent cells.
... Several reports have obtained similar experimental results to support our findings. For instance, Martínez-Zamudio et al. (2020) reported that AP-1 can imprint a reversible transcriptional program on senescent cells (Table 2). Chao Zhang et al. (2020) found that the increased openness of chromatin facilitated the binding of the motile transcription factor ATF3, which promoted cell aging. ...
Age is a significant contributing factor to the occurrence and progression of cardiovascular disease (CVD). Pharmacological treatment can effectively alleviate CVD symptoms caused by aging. However, 90% of the drugs have failed in clinics because of the loss of drug effects or the occurrence of the side effects. One of the reasons is the disparity between animal models used and the actual physiological levels in humans. Therefore, we integrated multiple datasets from single‐cell and bulk‐seq RNA‐sequencing data in rats, monkeys, and humans to identify genes and pathways with consistent/differential expression patterns across these three species. An approach called “Cross‐species signaling pathway analysis” was developed to select suitable animal models for drug screening. The effectiveness of this method was validated through the analysis of the pharmacological predictions of four known anti‐vascular aging drugs used in animal/clinical experiments. The effectiveness of drugs was consistently observed between the models and clinics when they targeted pathways with the same trend in our analysis. However, drugs might have exhibited adverse effects if they targeted pathways with opposite trends between the models and the clinics. Additionally, through our approach, we discovered four targets for anti‐vascular aging drugs, which were consistent with their pharmaceutical effects in literatures, showing the value of this approach. In the end, software was established to facilitate the use of “Cross‐species signaling pathway analysis.” In sum, our study suggests utilizing bioinformatics analysis based on disease characteristics can help in choosing more appropriate animal models.
... JUNB, which is also activated by JNK has been associated with growth limiting properties in PCa and its activation may explain the mechanism of JNK's tumorsuppression [22]. A recent study provides novel insights how the tumor-suppressive functions of AP-1 might be exerted, as JUN was particularly implicated as pioneering factor in bookmarking the enhancers of genes associated with the induction of the senescence program [23]. ...
... Our findings provide evidence that loss of JUN accompanied by reduced activation of STAT3 bypasses SASP and subsequently amplifies the tumor load in Jun PEΔ/Δ ; Pten PEΔ/Δ animals. We suggest an interplay of JUN and STAT3 mediating senescence-associated secretion of inflammatory factors in PCa in vivo, reinforcing JUN's proposed function as a pioneering factor of senescence [23]. ...
... This was evidenced by the association of the chromatin reader BRD4 with recruitment to enhancer regions activating SASP genes in senescent cells [65]. Recent findings have implicated AP-1 and in particular JUN as pioneering factors on a specific enhancer landscape essential for the execution of senescence-controlling programs [23]. In line with these results, we propose that loss of Pten coupled with an increase in JUN likely instigates a JUN-driven SASP phenotype. ...
Background
Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood.
Methods
We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment.
Results
Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth.
Conclusions
Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.
Graphical Abstract
... Different states may exist, ranging from "light" to "deep" senescence, likely differing in some aspects. A global epigenetic reprogramming occurs during time leading to the acquisition of novel cell functions that may still revert totally or only in part [60][61][62]. Tumor regrowth and/or acquisition of stemness features by senescent tumor cells after cell cycle reentry have been described and must be avoided [63]. In addition, a speculative idea is now linking senescence to cancer dormancy, with yet unexplored implications [64]. ...
Senescent cells have a profound impact on the surrounding microenvironment through the secretion of numerous bioactive molecules and inflammatory factors. The induction of therapy-induced senescence by anticancer drugs is known, but how senescent tumor cells influence the tumor immune landscape, particularly neutrophil activity, is still unclear. In this study, we investigate the induction of cellular senescence in breast cancer cells and the subsequent immunomodulatory effects on neutrophils using the CDK4/6 inhibitor palbociclib, which is approved for the treatment of breast cancer and is under intense investigation for additional malignancies. Our research demonstrates that palbociclib induces a reversible form of senescence endowed with an inflammatory secretome capable of recruiting and activating neutrophils, in part through the action of interleukin-8 and acute-phase serum amyloid A1. The activation of neutrophils is accompanied by the release of neutrophil extracellular trap and the phagocytic removal of senescent tumor cells. These findings may be relevant for the success of cancer therapy as neutrophils, and neutrophil-driven inflammation can differently affect tumor progression. Our results reveal that neutrophils, as already demonstrated for macrophages and natural killer cells, can be recruited and engaged by senescent tumor cells to participate in their clearance. Understanding the interplay between senescent cells and neutrophils may lead to innovative strategies to cope with chronic or tumor-associated inflammation.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00262-024-03695-5.
... Notch signalling is crucial for the switch from an early (for example, TGFβ) to a late (for example, IL-6 and IL-8) SASP by suppressing C/EBPβ, which further interferes with IL-1α and NF-κB 105,132 . A multi-omics study has shown that the transcription factor activator protein 1 (AP1) defines the temporal dynamics of the senescence-associated transcriptional network, including the SASP 133 . Although the short duration of the experiments (144 h) and the analysis of only transcriptomes do not allow a comprehensive characterization of the dynamics of the different factors secreted by senescent cells, this study 133 suggests that mathematical modelling is needed to better understand the SASP. ...
... A multi-omics study has shown that the transcription factor activator protein 1 (AP1) defines the temporal dynamics of the senescence-associated transcriptional network, including the SASP 133 . Although the short duration of the experiments (144 h) and the analysis of only transcriptomes do not allow a comprehensive characterization of the dynamics of the different factors secreted by senescent cells, this study 133 suggests that mathematical modelling is needed to better understand the SASP. ...
Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions.
... The SASP can contribute to tumour suppression by enhancing immune cell recruitment (Kale et al., 2020;Xue et al., 2007), but it can also promote tumour growth (Kuilman et al., 2008), and immunosuppression (Ruhland et al., 2016). Activation of SASPrelated genes is primarily driven by the transcription factors (TFs) NF-κB (subunit p65) and C/EBPβ (Chien et al., 2011;Kuilman et al., 2008) and is accompanied by substantial changes in the landscape of active enhancers (Martínez-Zamudio et al., 2020;Tasdemir et al., 2016). ...
... Both categories of senescent dependent peaks are enriched in binding motifs for components of the AP-1 complex ( Figure 1E). AP-1 acts as a pioneer TF, premarking prospective senescence enhancers (Martínez-Zamudio et al., 2020). This suggests that the initial shaping of the senescence enhancer landscape by AP-1 is unaffected by TPR knockdown. ...
During oncogene-induced senescence there are striking changes in the structure of the nucleus and the organisation of heterochromatin. This is accompanied by activation of a pro-inflammatory gene expression programme - the the senescence associated secretory phenotype (SASP) - driven by transcription factors such as NF-κB. Here we show that TPR, a protein of the nuclear pore complex basket, is required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of TBK1 signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. These cytoplasmic chromatin fragments appear to lack nuclear pore components. Our data suggest that TPR at the nuclear pore is involved in the loss of structural integrity of the nuclear periphery during senescence. We propose that this acts as a trigger for activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP, during senescence.
... In resistant genotoxically-treated cancer systems, the outcome of survivors is usually low but inevitable [30,39,40]. Therefore, the data of [41] inducing accelerated senescence in vitro in WI-38 cells by mutant RAS or RAF gene transfection that showed the pioneering role of the AP-1 complex in this response is highly informative. In line with our findings, the reproductive modules marked by oestrogen and androgen receptors were also found induced there. ...
The early stress response by AP-1 (FOS/JUN), supported by upregulation of c-Myc and involved in cell-fate changes and adaptation to hostile environments, is increased in cancer. The review shows the biphasic character of this response with negative feed-back typically lasting a few hours as a feature of the genome regulation by self-organising criticality. It involves rapid splitting of the pericentromeric heterochromatin clusters, opening of the active chromatin, and a massive transcription acceleration wave. Phylostratigraphic analysis revealed that AP-1 genes evolved in the Cambrian explosion ~500 Mya integrating the protein interaction networks of reproduction including proto-placenta intertwined with cytokine and immunity pathways, sex determination, oocyte maturation, and embryonal stemness. The peak of this response as part of accelerated cell senescence led by AP-1 and IL-1β was found in breast cancer cell-line resistant to doxorubicin. Adaptability of aggressive cancer to treatments can be explained by emergent stress response evolutionarily protecting reproduction
... To fulfill the genetic program of senescence, cells undergo timely accurate epigenetic resetting [6]. This reorganization involves the restructuring of proximal and distal regulatory elements (promoters and enhancers) with the stabilization of new super-enhancers (SEs) [7][8][9]. ...
An important epigenetic switch marks the onset and maintenance of senescence. This allows transcription of the genetic programs that arrest the cell cycle and alter the microenvironment. Transcription of endogenous retroviruses (ERVs) is also a consequence of this epigenetic switch. In this manuscript, we have identified a group of ERVs that are epigenetically silenced in proliferating cells but are upregulated during replicative senescence or during various forms of oncogene-induced senescence, by RAS and Akt, or after HDAC4 depletion. In a HDAC4 model of senescence, removal of the repressive histone mark H3K27me3 is the plausible mechanism that allows the transcription of intergenic ERVs during senescence. We have shown that ERVs contribute to the accumulation of dsRNAs in senescence, which can initiate the antiviral response via the IFIH1-MAVS signaling pathway and thus contribute to the maintenance of senescence. This pathway, and MAVS in particular, plays an active role in shaping the microenvironment and maintaining growth arrest, two essential features of the senescence program.
... 4E and 5D).We next sought to determine the extent to which the senescence phenotype induced by INX-315 treatment of CDK4/6 inhibitor-resistant tumors was similar to, or distinct from, CDK4/6 inhibitor-induced senescence in non-resistant tumor cells. Given the critical role of chromatin remodeling in governing the senescence phenotype(29,30,37), we performed the Assay for Transposase-Accessible Chromatin with Sequencing (ATAC-Seq) on (i) parental cells treated with control vehicle or abemaciclib; (ii) abemaciclib-and abemaciclib/fulvestrant-resistant cells treated with control vehicle or INX-315. Chromatin regions that became less accessible after abemaciclib treatment of parental cells also showed reduced accessibility after INX-315 treatment of resistant cells and were heavily enriched for E2F target gene promoters or non-promoter regions proximal to those genes (Supplementary Figs. ...
Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacologic inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent CDK2 inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX), and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypophosphorylation and therapy-induced senescence (TIS) in CCNE1-amplified tumors, leading to durable control of tumor growth; (ii) overcomes breast cancer resistance to CDK4/6i, restoring cell cycle control while reinstating the chromatin architecture of CDK4/6i-induced TIS; and (iii) delays the onset of CDK4/6i resistance in breast cancer by driving deeper suppression of E2F targets. Our results support the clinical development of selective CDK2 inhibitors.
Significance
INX-315 is a novel, selective inhibitor of CDK2. Our preclinical studies demonstrate activity for INX-315 in both CCNE1-amplified cancers and CDK4/6i–resistant breast cancer. In each case, CDK2 inhibition induces cell cycle arrest and a phenotype resembling cellular senescence. Our data support the development of selective CDK2 inhibitors in clinical trials.
... Even though some types of senescence show significant alterations in the chromatin landscape and share senescence effector pathways, transcription factors regulating downstream transcriptional programs in different senescence scenarios are always expressed in a tissue-specific manner. For example, studies on OIS and replicative senescence performed in distinct cells have revealed a role for the AP-1 family in reshaping open chromatin upon senescence entry, which is in accordance with the enrichment of the bZIP family (a total set of AP-1) at SAAs discovered in our study [37,38] (Fig. 4B). Although we have subsequently excluded AP-1 function from mediating the SAA landscape, it was previously uncovered that different members, including c-JUN and ATF3, participate in chromatin remodeling, indicating the identities of the drivers involved and their possible functional combinations across types of cells and senescence. ...
Dramatic alterations in epigenetic landscapes are known to impact genome accessibility and transcription. Extensive evidence demonstrates that senescent cells undergo significant changes in chromatin structure; however, the mechanisms underlying the crosstalk between epigenetic parameters and gene expression profiles have not been fully elucidated. In the present study, we delineate the genome-wide redistribution of accessible chromatin regions that lead to broad transcriptome effects during senescence. We report that distinct senescence-activated accessibility regions (SAAs) are always distributed in H3K27ac-occupied enhancer regions, where they are responsible for elevated flanking senescence-associated secretory phenotype (SASP) expression and aberrant cellular signaling relevant to SASP secretion. Mechanistically, a single transcription factor, TEAD4, moves away from H3K27ac-labled SAAs to allow for prominent chromatin accessibility reconstruction during senescence. The enhanced SAAs signal driven by TEAD4 suppression subsequently induces a robust increase in the expression of adjacent SASP genes and the secretion of downstream factors, which contribute to the progression of senescence. Our findings illustrate a dynamic landscape of chromatin accessibility following senescence entry, and further reveal an insightful function for TEAD4 in regulating the broad chromatin state that modulates the overall transcriptional program of SASP genes.
Electronic supplementary material
The online version of this article (10.1007/s00018-023-04980-9) contains supplementary material, which is available to authorized users.
