Writing histone monoubiquitination in human malignancy—The role of RING finger E3 ubiquitin ligases

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. There is growing evidence highlighting the importance of monoubiquitination as part of the histone code. Monoubiquitination, the covalent attachment of a single ubiquitin molecule at specific lysines of histone tails, has been associated with transcriptional elongation and the DNA damage response. Sites function as scaffolds or docking platforms for proteins involved in transcription or DNA repair; however, not all sites are equal, with some sites resulting in actively transcribed chromatin and others associated with gene silencing. All events are written by E3 ubiquitin ligases, predominantly of the RING (really interesting new gene) finger type. One of the most well-studied events is monoubiquitination of histone H2B at lysine 120 (H2Bub1), written predominantly by the RING finger complex RNF20-RNF40 and generally associated with active transcription. Monoubiquitination of histone H2A at lysine 119 (H2AK119ub1) is also well-studied, its E3 ubiquitin ligase constituting part of thePolycomb Repressor Complex 1 (PRC1), RING1B-BMI1, associated with transcriptional silencing. Both modifications are activated as part of the DNA damage response. Histone monoubiquitination is a key epigenomic event shaping the chromatin landscape of malignancy and influencing how cells respond to DNA damage. This review discusses a number of these sites and the E3 RING finger ubiquitin ligases that write them

Histone Monoubiquitination in Chromatin Remodelling: Focus on the Histone H2B Interactome and Cancer.

Chromatin remodelling is a major mechanism by which cells control fundamental processes including gene expression, the DNA damage response (DDR) and ensuring the genomic plasticity required by stem cells to enable differentiation. The post-translational modification of histone H2B resulting in addition of a single ubiquitin, in humans at lysine 120 (K120; H2Bub1) and in yeast at K123, has key roles in transcriptional elongation associated with the RNA polymerase II-associated factor 1 complex (PAF1C) and in the DDR. H2Bub1 itself has been described as having tumour suppressive roles and a number of cancer-related proteins and/or complexes are recognised as part of the H2Bub1 interactome. These include the RING finger E3 ubiquitin ligases RNF20, RNF40 and BRCA1, the guardian of the genome p53, the PAF1C member CDC73, subunits of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodelling complex and histone methyltransferase complexes DOT1L and COMPASS, as well as multiple deubiquitinases including USP22 and USP44. While globally depleted in many primary human malignancies, including breast, lung and colorectal cancer, H2Bub1 is selectively enriched at the coding region of certain highly expressed genes, including at p53 target genes in response to DNA damage, functioning to exercise transcriptional control of these loci. This review draws together extensive literature to cement a significant role for H2Bub1 in a range of human malignancies and discusses the interplay between key cancer-related proteins and H2Bub1-associated chromatin remodelling

The effect of alpha(+)-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya

BACKGROUND: The alpha-thalassaemias are the commonest genetic disorders of humans. It is generally believed that this high frequency reflects selection through a survival advantage against death from malaria; nevertheless, the epidemiological description of the relationships between alpha-thalassaemia, malaria, and other common causes of child mortality remains incomplete. METHODS AND FINDINGS: We studied the alpha+-thalassaemia-specific incidence of malaria and other common childhood diseases in two cohorts of children living on the coast of Kenya. We found no associations between alpha+-thalassaemia and the prevalence of symptomless Plasmodium falciparum parasitaemia, the incidence of uncomplicated P. falciparum disease, or parasite densities during mild or severe malaria episodes. However, we found significant negative associations between alpha+-thalassaemia and the incidence rates of severe malaria and severe anaemia (haemoglobin concentration < 50 g/l). The strongest associations were for severe malaria anaemia (> 10,000 P. falciparum parasites/mul) and severe nonmalaria anaemia; the incidence rate ratios and 95% confidence intervals (CIs) for alpha+-thalassaemia heterozygotes and homozygotes combined compared to normal children were, for severe malaria anaemia, 0.33 (95% CI, 0.15,0.73; p = 0.006), and for severe nonmalaria anaemia, 0.26 (95% CI, 0.09,0.77; p = 0.015). CONCLUSIONS: Our observations suggest, first that selection for alpha+-thalassaemia might be mediated by a specific effect against severe anaemia, an observation that may lead to fresh insights into the aetiology of this important condition. Second, although alpha+-thalassaemia is strongly protective against severe and fatal malaria, its effects are not detectable at the level of any other malaria outcome; this result provides a cautionary example for studies aimed at testing malaria interventions or identifying new malaria-protective genes

Dental plaque as a biofilm and a microbial community – implications for health and disease

Dental plaque is a structurally- and functionally-organized biofilm. Plaque forms in an ordered way and has a diverse microbial composition that, in health, remains relatively stable over time (microbial homeostasis). The predominant species from diseased sites are different from those found in healthy sites, although the putative pathogens can often be detected in low numbers at normal sites. In dental caries, there is a shift toward community dominance by acidogenic and acid-tolerating species such as mutans streptococci and lactobacilli, although other species with relevant traits may be involved. Strategies to control caries could include inhibition of biofilm development (e.g. prevention of attachment of cariogenic bacteria, manipulation of cell signaling mechanisms, delivery of effective antimicrobials, etc.), or enhancement of the host defenses. Additionally, these more conventional approaches could be augmented by interference with the factors that enable the cariogenic bacteria to escape from the normal homeostatic mechanisms that restrict their growth in plaque and out compete the organisms associated with health. Evidence suggests that regular conditions of low pH in plaque select for mutans streptococci and lactobacilli. Therefore, the suppression of sugar catabolism and acid production by the use of metabolic inhibitors and non-fermentable artificial sweeteners in snacks, or the stimulation of saliva flow, could assist in the maintenance of homeostasis in plaque. Arguments will be presented that an appreciation of ecological principles will enable a more holistic approach to be taken in caries control

Tissue biomarkers of breast cancer and their association with conventional pathologic features

Background:Tissue protein expression profiling has the potential to detect new biomarkers to improve breast cancer (BC) diagnosis, staging, and prognostication. This study aimed to identify tissue proteins that differentiate breast cancer tissue from healthy breast tissue using protein chip mass spectrometry and to examine associations with conventional pathological features.Methods:To develop a training model, 82 BC and 82 adjacent unaffected tissue (AT) samples were analysed on cation-exchange protein chips by time-of-flight mass spectrometry. For validation, 89 independent BC and AT sample pairs were analysed.Results:From the protein peaks that were differentially expressed between BC and AT by univariate analysis, binary logistic regression yielded two peaks that together classified BC and AT with a ROC area under the curve of 0.92. Two proteins, ubiquitin and S100P (in a novel truncated form), were identified by liquid chromatography/tandem mass spectrometry and validated by immunoblotting and reactive-surface protein chip immunocapture. The combined marker panel was positively associated with high histologic grade, larger tumour size, lymphovascular invasion, ER and PR positivity, and HER2 overexpression, suggesting that it may be associated with a HER2-enriched molecular subtype of breast cancer.Conclusion:This independently validated protein panel may be valuable in the classification and prognostication of breast cancer patients. © 2013 Cancer Research UK. All rights reserved

Elevated levels of circulating microRNA-200 family members correlate with serous epithelial ovarian cancer

Background: There is a critical need for improved diagnostic markers for high grade serous epithelial ovarian cancer (SEOC). MicroRNAs are stable in the circulation and may have utility as biomarkers of malignancy. We investigated whether levels of serum microRNA could discriminate women with high-grade SEOC from age matched healthy volunteers.Methods: To identify microRNA of interest, microRNA expression profiling was performed on 4 SEOC cell lines and normal human ovarian surface epithelial cells. Total RNA was extracted from 500 μL aliquots of serum collected from patients with SEOC (n = 28) and age-matched healthy donors (n = 28). Serum microRNA levels were assessed by quantitative RT-PCR following preamplification. Results: microRNA (miR)-182, miR-200a, miR-200b and miR-200c were highly overexpressed in the SEOC cell lines relative to normal human ovarian surface epithelial cells and were assessed in RNA extracted from serum as candidate biomarkers. miR-103, miR-92a and miR -638 had relatively invariant expression across all ovarian cell lines, and with small-nucleolar C/D box 48 (RNU48) were assessed in RNA extracted from serum as candidate endogenous normalizers. No correlation between serum levels and age were observed (age range 30-79 years) for any of these microRNA or RNU48. Individually, miR-200a, miR-200b and miR-200c normalized to serum volume and miR-103 were significantly higher in serum of the SEOC cohort (P < 0.05; 0.05; 0.0005 respectively) and in combination, miR-200b + miR-200c normalized to serum volume and miR-103 was the best predictive classifier of SEOC (ROC-AUC = 0.784). This predictive model (miR-200b + miR-200c) was further confirmed by leave one out cross validation (AUC = 0.784). Conclusions: We identified serum microRNAs able to discriminate patients with high grade SEOC from age-matched healthy controls. The addition of these microRNAs to current testing regimes may improve diagnosis for women with SEOC. © 2012 Kan et al.; licensee BioMed Central Ltd

Brachial and Cerebrovascular Functions Are Enhanced in Postmenopausal Women after Ingestion of Chocolate with a High Concentration of Cocoa.

Background: Cocoa contains polyphenols that are thought to be beneficial for vascular health.Objective: We assessed the impact of chocolate containing distinct concentrations of cocoa on cerebrovascular function and cognition.Methods: Using a counterbalanced within-subject design, we compared the acute impact of consumption of energy-matched chocolate containing 80%, 35%, and 0% single-origin cacao on vascular endothelial function, cognition, and cerebrovascular function in 12 healthy postmenopausal women (mean ± SD age: 57.3 ± 5.3 y). Participants attended a familiarization session, followed by 3 experimental trials, each separated by 1 wk. Outcome measures included cerebral blood flow velocity (CBFv) responses, recorded before and during completion of a computerized cognitive assessment battery (CogState); brachial artery flow-mediated dilation (FMD); and hemodynamic responses (heart rate and blood pressure).Results: When CBFv data before and after chocolate intake were compared between conditions through the use of 2-factor ANOVA, an interaction effect (P = 0.003) and main effects for chocolate (P = 0.043) and time (P = 0.001) were evident. Post hoc analysis revealed that both milk chocolate (MC; 35% cocoa; P = 0.02) and dark chocolate (DC; 80% cocoa; P = 0.003) induced significantly lower cerebral blood flow responses during the cognitive tasks, after normalizing for changes in arterial pressure. DC consumption also increased brachial FMD compared with the baseline value before chocolate consumption (P = 0.002), whereas MC and white chocolate (0% cocoa) caused no change (P-interaction between conditions = 0.034).Conclusions: Consumption of chocolate containing high concentrations of cocoa enhanced vascular endothelial function, which was reflected by improvements in FMD. Cognitive function outcomes did not differ between conditions; however, cerebral blood flow responses during these cognitive tasks were lower in those consuming MC and DC. These findings suggest that chocolate containing high concentrations of cocoa may modify the relation between cerebral metabolism and blood flow responses in postmenopausal women. This trial was registered at www.ANZCTR.orgau as ACTRN12616000990426

The Upper Stratospheric Solar Cycle Ozone Response

The solar cycle (SC) stratospheric ozone response is thought to influence surface weather and climate. To understand the chain of processes and ensure climate models adequately represent them, it is important to detect and quantify an accurate SC ozone response from observations. Chemistry climate models (CCMs) and observations display a range of upper stratosphere (1–10 hPa) zonally averaged spatial responses; this and the recommended data set for comparison remains disputed. Recent data‐merging advancements have led to more robust observational data. Using these data, we show that the observed SC signal exhibits an upper stratosphere U‐shaped spatial structure with lobes emanating from the tropics (5–10 hPa) to high altitudes at midlatitudes (1–3 hPa). We confirm this using two independent chemistry climate models in specified dynamics mode and an idealized timeslice experiment. We recommend the BASICv2 ozone composite to best represent historical upper stratospheric solar variability, and that those based on SBUV alone should not be used

Non-lethal control of the cariogenic potential of an agent-based model for dental plaque

Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments