Integration of multi-omics analysis reveals metabolic alterations of B lymphocytes in systemic lupus erythematosus.

OBJECTIVE: To link changes in the B-cell transcriptome from systemic lupus erythematosus (SLE) patients with those in their macroenvironment, including cellular and fluidic components. METHODS: Analysis was performed on 363 patients and 508 controls, encompassing transcriptomics, metabolomics, and clinical data. B-cell and whole-blood transcriptomes were analysed using DESeq and GSEA. Plasma and urine metabolomics peak changes were quantified and annotated using Ceu Mass Mediator database. Common sources of variation were identified using MOFA integration analysis. RESULTS: Cellular macroenvironment was enriched in cytokines, stress responses, lipidic synthesis/mobility pathways and nucleotide degradation. B cells shared these pathways, except nucleotide degradation diverted to nucleotide salvage pathway, and distinct glycosylation, LPA receptors and Schlafen proteins. CONCLUSIONS: B cells showed metabolic changes shared with their macroenvironment and unique changes directly or indirectly induced by IFN-α signalling. This study underscores the importance of understanding the interplay between B cells and their macroenvironment in SLE pathology.

Cytotoxic Effects of Major and Emerging Mycotoxins on HepaRG Cells and Transcriptomic Response after Exposure of Spheroids to Enniatins B and B1.

Mycotoxins, produced by fungi, frequently occur at different stages in the food supply chain between pre- and postharvest. Globally produced cereal crops are known to be highly susceptible to contamination, thus constituting a major public health concern. Among the encountered mycotoxigenic fungi in cereals, Fusarium spp. are the most frequent and produce both regulated (i.e., T-2 toxin, deoxynivalenol -DON-, zearalenone -ZEA-) and emerging (i.e., enniatins -ENNs-, beauvericin -BEA-) mycotoxins. In this study, we investigated the in vitro cytotoxic effects of regulated and emerging fusariotoxins on HepaRG cells in 2D and 3D models using undifferentiated and differentiated cells. We also studied the impact of ENN B1 and ENN B exposure on gene expression of HepaRG spheroids. Gene expression profiling pinpointed the differentially expressed genes (DEGs) and overall similar pathways were involved in responses to mycotoxin exposure. Complement cascades, metabolism, steroid hormones, bile secretion, and cholesterol pathways were all negatively impacted by both ENNs. For cholesterol biosynthesis, 23/27 genes were significantly down-regulated and could be correlated to a 30% reduction in cholesterol levels. Our results show the impact of ENNs on the cholesterol biosynthesis pathway for the first time. This finding suggests a potential negative effect on human health due to the essential role this pathway plays.

Meta-Analysis Suggests That Intron Retention Can Affect Quantification of Transposable Elements from RNA-Seq Data.

Transposable elements (TEs), also known as "jumping genes", are repetitive sequences with the capability of changing their location within the genome. They are key players in many different biological processes in health and disease. Therefore, a reliable quantification of their expression as transcriptional units is crucial to distinguish between their independent expression and the transcription of their sequences as part of canonical transcripts. TEs quantification faces difficulties of different types, the most important one being low reads mappability due to their repetitive nature preventing an unambiguous mapping of reads originating from their sequences. A large fraction of TEs fragments localizes within introns, which led to the hypothesis that intron retention (IR) can be an additional source of bias, potentially affecting accurate TEs quantification. IR occurs when introns, normally removed from the mature transcript by the splicing machinery, are maintained in mature transcripts. IR is a widespread mechanism affecting many different genes with cell type-specific patterns. We hypothesized that, in an RNA-seq experiment, reads derived from retained introns can introduce a bias in the detection of overlapping, independent TEs RNA expression. In this study we performed meta-analysis using public RNA-seq data from lymphoblastoid cell lines and show that IR can impact TEs quantification using established tools with default parameters. Reads mapped on intronic TEs were indeed associated to the expression of TEs and influence their correct quantification as independent transcriptional units. We confirmed these results using additional independent datasets, demonstrating that this bias does not appear in samples where IR is not present and that differential TEs expression does not impact on IR quantification. We concluded that IR causes the over-quantification of intronic TEs and differential IR might be confused with differential TEs expression. Our results should be taken into account for a correct quantification of TEs expression from RNA-seq data, especially in samples in which IR is abundant.

Metabolic Program of Regulatory B Lymphocytes and Influence in the Control of Malignant and Autoimmune Situations.

Metabolic pathways have been studied for a while in eukaryotic cells. During glycolysis, glucose enters into the cells through the Glut1 transporter to be phosphorylated and metabolized generating ATP molecules. Immune cells can use additional pathways to adapt their energetic needs. The pentose phosphate pathway, the glutaminolysis, the fatty acid oxidation and the oxidative phosphorylation generate additional metabolites to respond to the physiological requirements. Specifically, in B lymphocytes, these pathways are activated to meet energetic demands in relation to their maturation status and their functional orientation (tolerance, effector or regulatory activities). These metabolic programs are differentially involved depending on the receptors and the co-activation molecules stimulated. Their induction may also vary according to the influence of the microenvironment, i.e. the presence of T cells, cytokines … promoting the expression of particular transcription factors that direct the energetic program and modulate the number of ATP molecule produced. The current review provides recent advances showing the underestimated influence of the metabolic pathways in the control of the B cell physiology, with a particular focus on the regulatory B cells, but also in the oncogenic and autoimmune evolution of the B cells.