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Epithelioid sarcoma is a rare and aggressive mesenchymal tumour, the genetic hallmark of which is the loss of expression of SMARCB1, a key member of the SWItch/Sucrose Non‐Fermentable (SWI/SNF) chromatin remodelling complex. Hampered by its rarity, epithelioid sarcoma has received little research attention and therapeutic options for this disease remain limited. SMARCB1‐deficient tumours also include malignant rhabdoid tumour, atypical teratoid and rhabdoid tumour, epithelioid malignant peripheral nerve sheath tumour, and poorly differentiated chordoma. Histologically, it can be challenging to distinguish epithelioid sarcoma from malignant rhabdoid tumour and other SMARCB1‐deficient tumours, whereas methylation profiling shows that they represent distinct entities and facilitates their classification. Methylation studies on SMARCB1‐deficient tumours, although not including epithelioid sarcomas, reported methylation subgroups which resulted in new clinical stratification and therapeutic approaches. In addition, emerging evidence indicates that immunotherapy, including immune checkpoint inhibitors, represents a promising therapeutic strategy for SMARCB1‐deficient tumours. Here, we show that some epithelioid sarcomas share methylation patterns of malignant rhabdoid tumours indicating that this could help to distinguish these entities and guide treatment. Using gene expression data, we also showed that the immune environment of epithelioid sarcoma is characterised by a predominance of CD8+ lymphocytes and M2 macrophages. These findings have potential implications for the management of patients with epithelioid sarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

The crumbs cell polarity complex plays a crucial role in apical–basal epithelial polarity, cellular adhesion, and morphogenesis. Homozygous variants in human CRB1 result in autosomal recessive Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP), with no established genotype–phenotype correlation. The associated protein complexes have key functions in developmental pathways; however, the underlying disease mechanism remains unclear. Using the oko meduzym289/m289 (crb2a−/−) zebrafish, we performed integrative transcriptomic (RNA‐seq data) and methylomic [reduced representation bisulphite sequencing (RRBS)] analysis of whole retina to identify dysregulated genes and pathways. Delayed retinal cell specification was identified in both the crb2a−/− zebrafish and CRB1 patient‐derived retinal organoids, highlighting the dysfunction of cell cycle modulation and epigenetic transcriptional control. Differential DNA methylation analysis revealed novel hypermethylated pathways involving biological adhesion, Hippo, and transforming growth factor β (TGFβ) signalling. By integrating gene expression with DNA methylation using functional epigenetic modules (FEM), we identified six key modules involving cell cycle control and disturbance of TGFβ, bone morphogenetic protein (BMP), Hippo, and SMAD protein signal transduction pathways, revealing significant interactome hotspots relevant to crb2a function and confirming the epigenetic control of gene regulation in early retinal development, which points to a novel mechanism underlying CRB1‐retinopathies. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Diagnosing bone and soft tissue neoplasms remains challenging because of the large number of subtypes, many of which lack diagnostic biomarkers. DNA methylation profiles have proven to be a reliable basis for the classification of brain tumours and, following this success, a DNA methylation‐based sarcoma classification tool from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg has been developed. In this study, we assessed the performance of their classifier on DNA methylation profiles of an independent data set of 986 bone and soft tissue tumours and controls. We found that the 'DKFZ Sarcoma Classifier' was able to produce a diagnostic prediction for 55% of the 986 samples, with 83% of these predictions concordant with the histological diagnosis. On limiting the validation to the 820 cases with histological diagnoses for which the DKFZ Classifier was trained, 61% of cases received a prediction, and the histological diagnosis was concordant with the predicted methylation class in 88% of these cases, findings comparable to those reported in the DKFZ Classifier paper. The classifier performed best when diagnosing mesenchymal chondrosarcomas (CHSs, 88% sensitivity), chordomas (85% sensitivity), and fibrous dysplasia (83% sensitivity). Amongst the subtypes least often classified correctly were clear cell CHSs (14% sensitivity), malignant peripheral nerve sheath tumours (27% sensitivity), and pleomorphic liposarcomas (29% sensitivity). The classifier predictions resulted in revision of the histological diagnosis in six of our cases. We observed that, although a higher tumour purity resulted in a greater likelihood of a prediction being made, it did not correlate with classifier accuracy. Our results show that the DKFZ Classifier represents a powerful research tool for exploring the pathogenesis of sarcoma; with refinement, it has the potential to be a valuable diagnostic tool. [ABSTRACT FROM AUTHOR]

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Aim: The climate variability hypothesis (CVH) predicts that locations with reduced seasonal temperature variation select for species with narrower thermal ranges. Here we (a) test the CVH by assessing the effect of latitude and elevation on the thermal ranges of Andean vascular plant species and communities, and (b) assess tropical alpine plants vulnerability to warming based on their thermal traits. Location: High tropical Andes. Taxon: Vascular plants. Methods: Temperature data for 505 vascular plant species from alpine communities on 49 summits, were extracted from 29,627 georeferenced occurrences. Species thermal niche traits (TNTs) were estimated using bootstrapping for: minimum temperature, optimum (mean) temperature and breadth (maximum‐minimum). Plant community‐weighted scores were estimated using the TNTs of their constituent species. CVH was tested for species, biogeographical species groups and communities. Vulnerability to global warming was assessed for species, biogeographical species groups and communities. Results: Species restricted to the equator showed narrower thermal niche breadth than species whose ranges stretch far from the equator, however, no difference in niche breadth was found across summits' elevation. Biogeographical species groups distributed close to the equator and restricted to alpine regions showed narrower niche breadth than those with broader ranges. Community‐weighted scores of thermal niche breadth were positively related to distance from equator but not to elevation. Based on their TNTs, species restricted to equatorial latitudes and plant communities dominated by these species were identified as the most vulnerable to the projected 1.5°C warming, due to a potentially higher risk of losing thermal niche space. Main conclusions: Our study confirms that the CVH applies to high tropical Andean plant species and communities, where latitude has a strong effect on the thermal niche breadth. TNTs are identified as suitable indicators of species' vulnerability to warming and are suggested to be included in long‐term biodiversity monitoring in the Andes. [ABSTRACT FROM AUTHOR]

Controlling the functional dynamics of DNA within living cells is essential in biomedical research. Epigenetic modifications such as DNA methylation play a key role in this endeavour. DNA methylation can be controlled by genetic means. Yet there are few chemical tools available for the spatial and temporal modulation of this modification. Herein, we present a small‐molecule approach to modulate DNA methylation with light. The strategy uses a photo‐tuneable version of a clinically used drug (5‐aza‐2′‐deoxycytidine) to alter the catalytic activity of DNA methyltransferases, the enzymes that methylate DNA. After uptake by cells, the photo‐regulated molecule can be light‐controlled to reduce genome‐wide DNA methylation levels in proliferating cells. The chemical tool complements genetic, biochemical, and pharmacological approaches to study the role of DNA methylation in biology and medicine. [ABSTRACT FROM AUTHOR]

Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological variability. An improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra‐ and inter‐individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine. [ABSTRACT FROM AUTHOR]

The putative cannabinoid receptor GPR55 has been shown to play a tumor-promoting role in various cancers, and is involved in many physiological and pathological processes of the gastrointestinal (GI) tract. While the cannabinoid receptor 1 (CB1) has been reported to suppress intestinal tumor growth, the role of GPR55 in the development of GI cancers is unclear. We, therefore, aimed at elucidating the role of GPR55 in colorectal cancer (CRC), the third most common cancer worldwide. Using azoxymethane (AOM)- and dextran sulfate sodium (DSS)-driven CRC mouse models, we found that GPR55 plays a tumor-promoting role that involves alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor tissues. Concomitantly, expression levels of COX-2 and STAT3 were reduced in tumor tissue of GPR55 knockout mice, indicating reduced presence of tumor-promoting factors. By employing the experimental CRC models to CB1 knockout and CB1/GPR55 double knockout mice, we can further show that GPR55 plays an opposing role to CB1. We report that GPR55 and CB1 mRNA expression are differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 and GPR55 was also differentially regulated in human CRC tissue compared to control samples. Collectively, our data suggest that GPR55 and CB1 play differential roles in colon carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor. [ABSTRACT FROM AUTHOR]

The high tropical Andes host one of the richest alpine floras of the world, with exceptionally high levels of endemism and turnover rates. Yet, little is known about the patterns and processes that structure altitudinal and latitudinal variation in plant community diversity. Herein we present the first continental-scale comparative study of plant community diversity on summits of the tropical Andes. Data were obtained from 792 permanent vegetation plots (1 m2) within 50 summits, distributed along a 4200 km transect; summit elevations ranged between 3220 and 5498 m a.s.l. We analyzed the plant community data to assess: 1) differences in species abundance patterns in summits across the region, 2) the role of geographic distance in explaining floristic similarity and 3) the importance of altitudinal and latitudinal environmental gradients in explaining plant community composition and richness. On the basis of species abundance patterns, our summit communities were separated into two major groups: Puna and Páramo. Floristic similarity declined with increasing geographic distance between study-sites, the correlation being stronger in the more insular Páramo than in the Puna (corresponding to higher species turnover rates within the Páramo). Ordination analysis (CCA) showed that precipitation, maximum temperature and rock cover were the strongest predictors of community similarity across all summits. Generalized linear model (GLM) quasi-Poisson regression indicated that across all summits species richness increased with maximum air temperature and above-ground necromass and decreased on summits where scree was the dominant substrate. Our results point to different environmental variables as key factors for explaining vertical and latitudinal species turnover and species richness patterns on high Andean summits, offering a powerful tool to detect contrasting latitudinal and altitudinal effects of climate change across the tropical Andes. [ABSTRACT FROM AUTHOR]

Aims The high plant species diversity of tropical mountain forests is coupled with high habitat heterogeneity along gradients in elevation and topography. We quantified the effects of elevation, topography and forest edge on habitat conditions and woody plant diversity of tropical montane forest fragments. Location Tropical montane forest fragments, ' Yungas', Bolivia. Methods We measured microclimate and sampled soil properties and woody vegetation at forest edges and in the forest interior on ridges and in gorges along an elevational gradient of 600 m. We analysed effects of elevation, topography and forest edge on habitat conditions (i.e. microclimate, soil properties and forest structure), species richness, evenness and composition with linear mixed effects models and detrended correspondence analysis ( DCA). Results Changes in habitat conditions were weaker along the elevational gradient than between forest interior and forest edge and between different topographies. Species richness was not affected by any gradient, while species evenness was reduced at forest edges. All three gradients affected species composition, while effects of topography and forest edge were stronger than that of elevation. Conclusions In general, effects of the 600-m elevational gradient were weak compared to effects of forest edge and topography. Edge effects shifted species composition towards pioneer species, while topographical heterogeneity is particularly important for generating high diversity in montane forests. These results underscore that edge effects have severe consequences in montane forest remnants and that small-scale variation between topographical microhabitats should be considered in studies that predict monotonous upslope migrations of plant species in tropical montane forests due to global warming. [ABSTRACT FROM AUTHOR]

The article focuses on study related to multiple myeloma and role of global hypomethylation in myeloma which is associated with poor prognosis. Topics discussed include methylation patterns which include global hypomethylation in asymptomatic myeloma and hypermethylation in symptomatic myeloma; role of transcription start site in regulation of gene expression; and relevance of gene promoter hypomethylation to survival outcomes in myeloma patients.

The major histocompatibility complex (MHC) contain genes which play a key role in immune response and mate choice, and are therefore of functional importance to molecular ecologists. Here we describe the design of 10 MHC Class I-associated microsatellite loci from the tammar wallaby. All 10 loci are highly polymorphic, with the expected heterozygosity ranging from 0.547 to 0.919. Six loci successfully cross-amplify in other macropodid species. These microsatellites will serve as useful tools for studying the level of MHC diversity, the impact of selection on genetic variation and the unique structure of the tammar wallaby MHC. [ABSTRACT FROM AUTHOR]

The two sets of inhibitory and activating natural killer (NK) receptor genes belong either to the IG or to the C-type lectin superfamilies. Both are extensive and diverse, comprising genes of varying degrees of relatedness, indicative of a process of iterative duplication. We have constructed gene maps to help understand how and when NK receptor genes developed and the nature of their polymorphism. A cluster of over 15 C-type lectin genes, the natural killer complex is located on human chromosome 12p13.1, synthetic with a region in mouse that borders multiple Ly49 loci. The equivalent locus in man is occupied by a single pseudogene, LY49L. The immunoglobulin superfamily of loci, the leukocyte receptor complex (LRC), on chromosome 19q13.4, contains many polymorphic killer cell immunoglobulin-like receptor (KIR) genes as well as multiple related sequences. These include immunoglobulin-like transcript (ILT) (or leukocyte immunoglobulin-like receptor genes), leukocyte-associated inhibitory receptor genes (LAIR), NKp46, FcαR and the platelet gylcoprotein receptor VI locus, which encodes a collagen-binding molecule. KIRs are expressed mostly on NK cells and some T cells. The other LRC loci are more widely expressed. Further centromeric of the LRC are sets of additional loci with weak sequence similarity to the KIRs, including the extensive CD66(CEA) and Siglec families. The LRC-syntenic region in mice contains no orthologues of KIRs. Some of the KIR genes are highly polymorphic in terms of sequence as well as for presence/absence of genes on different haploypes. Some anchor loci, such as KIR2DL4, are present on most haplotypes. A few ILT loci, such as ILT5 and ILT8, are polymorphic, but only ILT6 exhibits presence/absence variation. This knowledge of the genomic organisation of the extensive NK superfamilies underpins efforts to understand the functions of the encoded NK receptor molecules. It leads to the conclusion that the functional homology of human KIR and mo [ABSTRACT FROM AUTHOR]

We present the genomic organisation of the extended class II region of the human MHC. This initial sequence, which is nearing completion, spans about 1.2 Mbp and is at present a composite of more than one haplotype. The sequencing of single haplotypes is planned for the future. The current sequence encompasses all of the known class II genes at the DP, DO, DM, DQ and DR loci as well as the transporter associated with antigen processing (TAP)/low molecular weight protein (LMP) antigen processing genes and the Tapasin locus, at the extended centromeric end. INSET: Feature map of the MHC class II region. [ABSTRACT FROM AUTHOR]

Some years ago, we used out data for class I genes, proteins and peptide-binding specificities to develop the hypothesis that the chicken B-F/B-L region represents a "minimal essential MHC". In this view, the B locus contains the classical (highly expressed and polymorphic) class I α and class II β multigene families, which are reduced to one or two members, with many other genes moved away or deleted from the chicken genome together. We found that a single dominantly expressed class I gene determines the immune response to certain infectious pathogens, due to peptide-binding specificity and cell-surface expression level. This stands in stark contrast to well-studied mammals like humans and mice, in which every haptotype is more-or-less responsive to every pathogen and vaccine, presumably due to the multigene family of MHC molecules present. In order to approach the basis for a single dominantly expressed class I molecule, we have sequenced a portion of the B complex and examined the location and polymorphism of the class I (B-F) &alpha, TAP and class II (B-L) β genes. The region is remarkably compact and simple, with many of the genes expected from the MHC of mammals absent, including LMP, class II α and DO genes as we as most class III region genes. However, unexpected genes were present, including tapasin and putative natural killer receptor genes. The region is also organized differently from mammals, with the TAPs in between the class I genes, the tapasin gene in between the class II (B-L) β genes, and the C4 gene outside of the class I α and class II β genes. The close proximity of TAP and class I &alpha genes leads to the possibility of co-evolution, which can drive the use of single dominantly expressed class I molecule with peptide-binding specificity like the... [ABSTRACT FROM AUTHOR]

Objective: A significant proportion of HNSCC is caused by human papillomavirus. Patients diagnosed with this subtype have a significantly better outcome. It is the aim of the UCL Head and Neck Cancer Epigenome Project to generate and analyze comprehensive, genome‐wide profiles of epigenetic aberrations in this specific type of human cancer. Method: Whole‐genome DNA methylation (methylome) analysis of 3 HPV positive and 3 HPV negative frozen HNSCC samples (obtained from the UCL Head and Neck Cancer Tissue Bank as part of a larger discovery set) was conducted using methylated DNA immunoprecipitation coupled with next‐generation sequencing (MeDIP‐Seq). Results: On average, each sample in the pilot phase generated 2 x 107 sequencing reads and 70% coverage of all CpG sites within the host genome. HPV type 16 was observed in all HPV positive samples and, interestingly, methylated regions of this virus were identified—most notably at genes E1 and L1 (previously shown to have been methylated in cervical cancer). We also detected multiple methylation changes between HPV positive and HPV negative host's methylomes, of which a significant proportion mapped to genes previously shown to display down‐regulated expression in transcriptionally active HPV positive oropharyngeal cancer. Conclusion: The observed epigenetic differences between the 2 types might explain the different clinical behavior of HPV‐associated HNSCC. Although preliminary, these pilot data are encouraging with respect to the possibility of identifying potential diagnostic and prognostic markers, as well as putative therapeutic targets in this subtype of HNSCC. [ABSTRACT FROM AUTHOR]