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Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously. Adding to the recent debate on the role of epithelial–mesenchymal transition (EMT) in cancer cell invasion and metastasis, Brabletz and colleagues show that the EMT-inducing transcription factor Zeb1 drives pancreatic tumorigenesis and metastasis.

Despite the availability of batch effect correcting algorithms (BECA), no comprehensive tool that combines batch correction and evaluation of the results exists for microbiome datasets. This work outlines the Microbiome Batch Effects Correction Suite development that integrates several BECAs and evaluation metrics into a software package for the statistical computation framework R.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome. However, the identity of gut microbes associated with disease risk, their mechanisms of action, and the interactions with host genetics remain obscure. To address these questions, we utilized the principal autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), together with a genetically diverse mouse model representing 29 unique host genotypes, interrogated by microbiome sequencing and targeted microbiome manipulation. We identified specific gut bacteria and their metabolic functions associated with EAE susceptibility, implicating short-chain fatty acid metabolism as a key element conserved across multiple host genotypes. In parallel, we used a reductionist approach focused on two of the most disparate phenotypes identified in our screen. Manipulation of the gut microbiome by transplantation and cohousing demonstrated that transfer of these microbiomes into genetically identical hosts was sufficient to modulate EAE susceptibility and systemic metabolite profiles. Parallel bioinformatic approaches identified Lactobacillus reuteri as a commensal species unexpectedly associated with exacerbation of EAE in a genetically susceptible host, which was functionally confirmed by bacterial isolation and commensal colonization studies. These results reveal complex interactions between host genetics and gut microbiota modulating susceptibility to CNS autoimmunity, providing insights into microbiome-directed strategies aimed at lowering the risk for autoimmune disease and underscoring the need to consider host genetics and baseline gut microbiome composition.

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M pro ) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M pro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M pro -induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19. A novel study led by scientists in Lübeck, Germany, shows that SARS-CoV-2-infected brain endothelial cells undergo cell death due to the cleavage of NEMO by the viral protease M pro , potentially causing cerebral COVID-19 and ‘long COVID’ symptoms.

The pemphigus family of skin blistering diseases represents a rare yet potentially life-threatening condition characterized by multiple known genetic loci associated with other autoimmune disorders. While several studies have empirically indicated an increased risk of developing additional autoimmune diseases in individuals with pemphigus, the scarcity of data and the rarity of pemphigus have hindered efforts to establish and generalize these associations across diverse populations. In this study, we analyzed a dataset comprising 126 million patients, including 18,000 with pemphigus, to assess the likelihood of developing any of 74 autoimmune diseases following a diagnosis of pemphigus. For a subset of 26 diseases from this list with adequate patient numbers, we conducted further case-control retrospective analyses to quantify the odds and hazard ratios of developing comorbid conditions across various ethnicities. Our findings reveal highly significant and generalizable associations between pemphigus and pemphigoid diseases, discoid lupus erythematosus, lichen planus, and undifferentiated connective tissue disease, among others.

Exploration of genetic variant-to-gene relationships by quantitative trait loci such as expression QTLs is a frequently used tool in genome-wide association studies. However, the wide range of public QTL databases and the lack of batch annotation features complicate a comprehensive annotation of GWAS results. In this work, we introduce the tool “Qtlizer” for annotating lists of variants in human with associated changes in gene expression and protein abundance using an integrated database of published QTLs. Features include incorporation of variants in linkage disequilibrium and reverse search by gene names. Analyzing the database for base pair distances between best significant eQTLs and their affected genes suggests that the commonly used cis -distance limit of 1,000,000 base pairs might be too restrictive, implicating a substantial amount of wrongly and yet undetected eQTLs. We also ranked genes with respect to the maximum number of tissue-specific eQTL studies in which a most significant eQTL signal was consistent. For the top 100 genes we observed the strongest enrichment with housekeeping genes ( P  = 2 × 10 –6 ) and with the 10% highest expressed genes ( P  = 0.005) after grouping eQTLs by r 2  > 0.95, underlining the relevance of LD information in eQTL analyses. Qtlizer can be accessed via https://genehopper.de/qtlizer or by using the respective Bioconductor R-package ( https://doi.org/10.18129/B9.bioc.Qtlizer ).

Type 2 Diabetes Mellitus has reached epidemic levels globally, and several studies have confirmed a link between gut microbial dysbiosis and aberrant glucose homeostasis among people with diabetes. While the assumption is that abnormal metabolomic signatures would often accompany microbial dysbiosis, the connection remains largely unknown. In this study, we investigated how diet changed the gut bacteriome, mycobiome and metabolome in people with and without type 2 Diabetes.1 Differential abundance testing determined that the metabolites Propionate, U8, and 2-Hydroxybutyrate were significantly lower, and 3-Hydroxyphenyl acetate was higher in the high fiber diet compared to low fiber diet in the healthy control group. Next, using multi-omics factor analysis (MOFA2), we attempted to uncover sources of variability that drive each of the different groups (bacterial, fungal, and metabolite) on all samples combined (control and DM II). Performing variance decomposition, ten latent factors were identified, and then each latent factor was tested for significant correlations with age, BMI, diet, and gender. Latent Factor1 was the most significantly correlated. Remarkably, the model revealed that the mycobiome explained most of the variance in the DM II group (12.5%) whereas bacteria explained most of the variance in the control group (64.2% vs. 10.4% in the DM II group). The latent Factor1 was significantly correlated with dietary intake ( q  < 0.01). Further analyses of the impact of bacterial and fungal genera on Factor1 determined that the nine bacterial genera ( Phocaeicola, Ligilactobacillus, Mesosutterella, Acidaminococcus, Dorea A, CAG-317, Caecibacter, Prevotella and Gemmiger ) and one fungal genus ( Malassezia furfur ) were found to have high factor weights (absolute weight > 0.6). Alternatively, a linear regression model was fitted per disease group for each genus to visualize the relationship between the factor values and feature abundances, showing Xylose with positive weights and Propionate, U8, and 2-Hydroxybutyrate with negative weights. This data provides new information on the microbially derived changes that influence metabolic phenotypes in response to different diets and disease conditions in humans.

Epstein–Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies.

Diabetes mellitus (DM) represents a major health problem in Egypt and worldwide, with increasing numbers of patients with prediabetes every year. Numerous factors, such as obesity, hyperlipidemia, and hypertension, which have recently become serious concerns, affect the complex pathophysiology of diabetes. These metabolic syndrome diseases are highly linked to genetic variability that drives certain populations, such as Egypt, to be more susceptible to developing DM. Here we conduct a comprehensive analysis to pinpoint the similarities and uniqueness among the Egyptian genome reference and the 1000-genome subpopulations (Europeans, Ad-Mixed Americans, South Asians, East Asians, and Africans), aiming at defining the potential genetic risk of metabolic syndromes. Selected approaches incorporated the analysis of the allele frequency of the different populations’ variations, supported by genotypes’ principal component analysis. Results show that the Egyptian’s reference metabolic genes were clustered together with the Europeans’, Ad-Mixed Americans’, and South-Asians’. Additionally, 8563 variants were uniquely identified in the Egyptian cohort, from those, two were predicted to cause structural damage, namely, CDKAL1: 6_21065070 (A > T) and PPARG: 3_12351660 (C > T) utilizing the Missense3D database. The former is a protein coding gene associated with Type 2 DM while the latter is a key regulator of adipocyte differentiation and glucose homeostasis. Both variants were detected heterozygous in two different Egyptian individuals from overall 110 sample. This analysis sheds light on the unique genetic traits of the Egyptian population that play a role in the DM high prevalence in Egypt. The proposed analysis pipeline -available through GitHub- could be used to conduct similar analysis for other diseases across populations.

Phenotypic conversion of tumor cells through epithelial-mesenchymal transition (EMT) requires massive gene expression changes. How these are brought about is not clear. Here we examined the impact of the EMT master regulator SNAIL1 on the FOXA family of transcription factors which are distinguished by their particular competence to induce chromatin reorganization for the activation of transcriptional enhancer elements. We show that the expression of SNAIL1 and FOXA genes is anticorrelated in transcriptomes of colorectal tumors and cell lines. In cellular EMT models, ectopically expressed Snail1 directly represses FOXA1 and triggers downregulation of all FOXA family members, suggesting that loss of FOXA expression promotes EMT. Indeed, cells with CRISPR/Cas9-induced FOXA-deficiency acquire mesenchymal characteristics. Furthermore, ChIP-seq data analysis of FOXA chromosomal distribution in relation to chromatin structural features which characterize distinct states of transcriptional activity, revealed preferential localization of FOXA factors to transcriptional enhancers at signature genes that distinguish epithelial from mesenchymal colon tumors. To validate the significance of this association, we investigated the impact of FOXA factors on structure and function of enhancers at the CDH1, CDX2 and EPHB3 genes. FOXA-deficiency and expression of dominant negative FOXA2 led to chromatin condensation at these enhancer elements. Site-directed mutagenesis of FOXA binding sites in reporter gene constructs and by genome-editing in situ impaired enhancer activity and completely abolished the active chromatin state of the EPHB3 enhancer. Conversely, expression of FOXA factors in cells with inactive CDX2 and EPHB3 enhancers led to chromatin opening and de novo deposition of the H3K4me1 and H3K27ac marks. These findings establish the pioneer function of FOXA factors at enhancer regions of epithelial genes and demonstrate their essential role in maintaining enhancer structure and function. Thus, by repressing FOXA family members, SNAIL1 targets transcription factors at strategically important positions in gene-regulatory hierarchies, which may facilitate transcriptional reprogramming during EMT.