Biology subjects

Salma, M.

Publications and source records attributed to Salma, M..

5 recordsLinked to original sources

bioRxiv2025

The methyl-CpG-binding protein 2 inhibits cGAS-associated signaling

The detection of cytosolic dsDNA is tightly regulated to avoid pathological inflammatory responses. A major pathway involved in their detection relies on the cyclic GMP-AMP synthase (cGAS) that triggers activation of the Stimulator of interferon genes (STING) which subsequently drives the expression of inflammatory genes and type I Interferons (IFNs). Here, we show that the methyl-CpG-binding protein 2 (MECP2), a major transcriptional regulator, controls dsDNA-associated inflammatory responses. We show that the presence of cytosolic dsDNA promotes MECP2 export from the nucleus to the cytosol where it interacts with dsDNA, dampening cGAS activation. Our data also indicate that MECP2 export from the nucleus partially phenocopies MECP2 deficiency, leading to the expression of inflammatory and interferon stimulated genes, enforcing an antiviral state. Finally, we also show that MECP2 displacement from the nucleus following dsDNA stimulation is sufficient to disrupt its canonical function, leading to the reactivation of otherwise repressed genes, such endogenous retroelements of the Long interspersed nuclear element-1 (LINE-1) family. Re-expression of the latter led to the accumulation of DNA species feeding cGAS-dependent signaling and can be dampened by reverse transcriptase inhibitors. We thus establish a previously unforeseen direct role of MECP2 in the regulation of the breadth and nature of dsDNA-associated inflammatory responses. Furthermore, our results suggest that targeting dsDNA-associated pathways or pharmacological inhibition of LINE-1 may bear therapeutic hopes for Rett syndrome (RTT) patients that present with MECP2 deficiency.

immunology↗

bioRxiv2025

In vivo deletion of a GWAS-identified Myb distal enhancer acts on Myb expression, globin switching, and clinical erythroid parameters in beta-thalassemia

Genome-wide association studies (GWAS) have identified numerous genetic variants linked to human diseases, mostly located in non-coding regions of the genome, particularly in putative enhancers. However, functional assessment of the non-coding GWAS variants has progressed at slow pace, since the functions of the vast majority of genomic enhancers have not been defined, impeding interpretation of disease-susceptibility variants. The HBS1L-MYB intergenic region harbors multiple SNPs associated with clinical erythroid parameters, including fetal hemoglobin levels, a feature impacting disease severity of beta-hemoglobinopathies such as sickle cell anemia and beta-thalassemia. HBS1L-MYB variants cluster in the vicinity of several MYB enhancers, altering MYB expression and globin switching. We and others have highlighted the conserved human MYB -84kb enhancer, known as the -81kb enhancer in the mouse, as likely candidate linked to these traits. We report here the generation of a Myb -81kb enhancer knock-out mouse model, and shed light for the first time on its impact on steady state erythropoiesis and in beta-thalassemia in vivo.

genetics↗

bioRxiv2024

VEXAS anemia is a mosaic erythroblastopenia

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently discovered autoinflammatory disorder linked to somatic mutations in the UBA1 gene, resulting in a profound cytoplasm-restricted defect in ubiquitylation. The disease is characterized by a macrocytic anemia that remains poorly understood. To investigate the erythroid lineage in VEXAS, we conducted a comprehensive study combining in vivo assessments of patients mature red cells and marrow erythroblasts, alongside in vitro base-editing models of erythropoiesis. Here we show that mature red cells do not exhibit ubiquitylation defects, and patient-derived bone marrow erythroblasts lack UBA1 mutations beyond the basophilic stage of erythroid differentiation. In vitro base editing of UBA1 variants in CD34+ primary cells resulted in high mortality during early erythroid differentiation, but not during monocytic differentiation. Edited erythroid precursors displayed TP53 overexpression linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia. We propose that VEXAS-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of the UBA1-WT compartment. These insights may aid clinicians in tailoring treatment strategies.

cell biology↗

bioRxiv2022

Var I Decrypt: a novel and user-friendly tool to explore and prioritize variants in whole-exome sequencing data

MotivationHigh throughput sequencing (HTS) offers unprecedented opportunities for the discovery of causative gene variants in multiple human disorders including cancers, and has revolutionized clinical diagnostics. However, despite more than a decade of use of HTS-based assays, extracting relevant functional information from whole exome sequencing (WES) data remains challenging, especially for non-specialists lacking in-depth bioinformatic skills. ResultsTo address this limitation, we developed Var|Decrypt, a web-based tool designed to greatly facilitate WES data browsing and analysis. Var|Decrypt offers a wide range of gene and variant filtering possibilities, clustering and enrichment tools, providing an efficient way to derive patient-specific functional information and to prioritize gene variants for functional analyses. We applied Var|Decrypt on WES datasets of 10 acute erythroid leukemia patients, a rare and aggressive form of leukemia, and recovered known disease oncogenes in addition to novel putative drivers. We additionally benchmarked Var|Decrypt on an independent dataset of ~90 multiple myeloma WES, recapitulating the identified deregulated genes and pathways, showing the general applicability and versatility of Var|Decrypt for WES analysis.

bioinformatics↗

bioRxiv2021

ONTdeCIPHER: An amplicon-based nanopore sequencing pipeline for tracking pathogen variants

MotivationAmplicon-based nanopore sequencing is increasingly used for molecular surveillance during epidemics (e.g. ZIKA, EBOLA) or pandemics (e.g. SARS-CoV-2). However, there is still a lack of versatile and easy-to-use tools that allow users with minimal bioinformatics skills to perform the main steps of downstream analysis, from quality testing to SNPs effect to phylogenetic analysis. ResultsHere, we present ONTdeCIPHER, an amplicon-based Oxford Nanopore Technology (ONT) sequencing pipeline to analyze the genetic diversity of SARS-CoV-2 and other pathogenes. Our pipeline integrates 13 bioinformatics tools. With a single command line and a simple configuration file, users can pre-process their data and obtain the sequencing statistics, reconstruct the consensus genome, identify variants and their effects for each viral isolate, infer lineage and, finally perform multi-sequence alignments and phylogenetic analyses. Availability and implementationONTdeCIPHER is available at https://github.com/emiracherif/ONTdeCIPHER Contactemira.cherif@ird.fr Supplementary informationSupplementary data are available at ...

bioinformatics↗