Senescence, a state of stable growth arrest, plays an important role in ageing and age‐related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up‐regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down‐regulates p16 levels and increases the pool of p16− p21− ‘reversed’ cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence.
Senescence occurs in response to a number of damaging stimuli to limit oncogenic transformation and cancer development. As no single, universal senescence marker has been discovered, the confident classification of senescence induction requires the parallel assessment of a series of hallmarks. Therefore, there is a growing need for “first-pass” tools of senescence identification to streamline experimental workflows and complement conventional markers. Here, we utilise a high content, multidimensional phenotypic profiling-based approach, to assess the morphological profiles of senescent cells induced via a range of stimuli. In the context of senescence, we refer to these as senescence-associated morphological profiles (SAMPs), as they facilitate distinction between senescent and proliferating cells. The complexity of the profiles generated also allows exploration of the heterogeneity both between models of senescence and within an individual senescence model, providing a level of insight at the single cell level. Furthermore, we also demonstrate that these models are applicable to the assessment of senescence in vivo , which remains a key challenge for the field. Therefore, we believe SAMPs has the potential to serve as a useful addition in the repertoire of senescence researchers, either as a first-pass tool or as part of the established senescence hallmarks.
Land-ocean dissolved organic matter (DOM) transport is a significant and changing term in global biogeochemical cycles which is increasing as a result of human perturbation, including land-use change. Knowledge of the behavior and fate of transported DOM is lacking, particularly in the tropics and subtropics where land-use change is occurring rapidly. We used Parallel Factor (PARAFAC) Analysis to investigate how land-use influenced the composition of the DOM pool along a subtropical land-use gradient (from near-pristine broadleaf forest to agri-urban settings) in Belize, Central America. Three humic-like and two protein-like components were identified, each of which was present across land uses and environments. Land-use mapping identified a strong (R 2 = 0.81) negative correlation between broadleaf forest and agri-urban land. All PARAFAC components were positively associated with agriurban land-use classes (cropland, grassland, and/or urban land), indicating that land-use change from forested to agri-urban exerts influence on the composition of the DOM pool. Humic-like DOM exhibited linear accumulation with distance downstream and behaved conservatively in the coastal zone whilst protein-like DOM exhibited nonlinear accumulation within the main river and nonconservative mixing in coastal waters, indicative of differences in reactivity. We used a hydrodynamic model to explore the potential of conservative humics to reach the region's environmentally and economically valuable coral reefs. We find that offshore corals experience short exposures (10 ± 11 days yr −1 ) to large (∼120%) terrigenous DOM increases, whilst nearshore corals experience prolonged exposure (113 ± 24 days yr −1 ) to relatively small (∼30%) terrigenous DOM increases. Plain Language SummaryThe transport of land-derived dissolved organic matter into the oceans plays a substantial and important role in the global carbon and nutrient cycles. Land-use change can alter the type and amount of material being transported, with widespread implications for downstream ecosystems. This is particularly true in the tropics and subtropics where land-use change is occurring most rapidly, and where research into its effects is often lacking. We investigated whether landuse had an effect on the type and amount of land-derived material found in a subtropical river system that is experiencing a rapid conversion from forest to agricultural and urban land-use. We found that streams draining agricultural and urban land contained more land-derived material than those draining forested land, and that a substantial fraction of this material reached the coastal environment. We estimated the frequency with which this land-derived material reached the region's environmentally and economically valuable coral reefs, and suggest that land-use-derived material reaches nearshore corals often and offshore corals rarely. FELGATE ET AL.
Melanocytes reside within the basal epidermis of human skin, and function to protect the skin from ultraviolet light through the production of melanin. Prolonged exposure of the skin to UV light can induce irreparable DNA damage and drive cells into senescence, a sustained cell cycle arrest that prevents the propagation of this damage. Senescent cells can also be detrimental and contribute to skin ageing phenotypes through their senescence-associated secretory phenotype. Senescent cells can act in both an autocrine and paracrine manner to produce widespread tissue inflammation and skin ageing. Recently, melanocytes have been identified as the main senescent cell population within the epidermis and have been linked to a variety of skin ageing phenotypes, such as epidermal thinning and the presence of wrinkles. However, the literature surrounding melanocyte senescence is limited and tends to focus on the role of senescence in the prevention of melanoma. Therefore, this review aims to explore the current understanding of the contribution of senescent melanocytes to human skin ageing.
Senescence is a widely appreciated tumour suppressive mechanism, which acts as a barrier to cancer development by arresting cell cycle progression in response to harmful stimuli. However, senescent cell accumulation becomes deleterious in aging and contributes to a wide range of age-related pathologies. Furthermore, senescence has beneficial roles and is associated with a growing list of normal physiological processes including wound healing and embryonic development. Therefore, the biological role of senescent cells has become increasingly nuanced and complex. The emergence of sophisticated, next-generation profiling technologies, such as single-cell RNA sequencing, has accelerated our understanding of the heterogeneity of senescence, with distinct final cell states emerging within models as well as between cell types and tissues. In order to explore data sets of increasing size and complexity, the senescence field has begun to employ machine learning (ML) methodologies to probe these intricacies. Most notably, ML has been used to aid the classification of cells as senescent, as well as to characterise the final senescence phenotypes. Here, we provide a background to the principles of ML tasks, as well as some of the most commonly used methodologies from both traditional and deep ML. We focus on the application of these within the context of senescence research, by addressing the utility of ML for the analysis of data from different laboratory technologies (microscopy, transcriptomics, proteomics, methylomics), as well as the potential within senolytic drug discovery. Together, we aim to highlight both the progress and potential for the application of ML within senescence research.
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