Biology subjects

Rihet, P.

Publications and source records attributed to Rihet, P..

3 recordsLinked to original sources

bioRxiv2025

Identification and Functional Characterization of Regulatory Variants in DPP9 Associated with COVID-19 Severity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to a wide-range of clinical outcomes, which have been extensively studied through genome-wide association studies (GWAS). Starting from lead genetic variants associated with COVID-19 infection and severity, we identified a subset of non-coding candidate variants with potential regulatory functions. Using bioinformatics analysis and functional screening in three cell lines, we prioritized two DPP9 variants within a haplotype that increases the risk of severe COVID-19. This haplotype exhibited increased regulatory activity and altered transcription factor binding, suggesting its role in influencing COVID-19 severity through modulation of DPP9 expression in immune and lung cell types. The interest of our study lies in the functional characterization of regulatory variants responsible for the higher levels of DPP9 and lung damage observed in patients with severe COVID-19. These findings advance our understanding of genetic risk factors for COVID-19 and highlight functional SNPs that may guide future therapeutic research.

genetics↗

bioRxiv2024

Unraveling a novel dual-function regulatory element showing epistatic interaction with a variant that escapes genome-wide association studies.

Regulation of gene expression has recently been complexified by the identification of Epromoters, a subset of promoters with enhancer function. Here, we uncovered the first dual cis-regulatory element, "ESpromoter," exhibiting both enhancer and silencer function, as a regulator of the nearby genes ATP2B4 and LAX1 in single human T cells. Through integrative approach, we pinpointed functional rs11240391, a severe malaria risk variant that escapes detection in genome-wide association studies, challenging conventional strategies for identifying causal variants. CRISPR-modified cells demonstrated the regulatory effect of ESpromoter and rs11240391 on LAX1 expression and T cell activation. Furthermore, our findings revealed an epistatic interaction between ESpromoter SNPs and rs11240391, impacting severe malaria susceptibility by further reducing LAX1 expression. This groundbreaking discovery challenges the conventional enhancer-silencer dichotomy. It highlights the sophistication of transcriptional regulation and argues for an integrated approach combining genetics, epigenetics, and genomics to identify new therapeutic targets for complex diseases. HIGHLIGHTSO_LINovel dual enhancer-silencer element (ESpromoter) in a single human cell type C_LIO_LIFunctional SNP for severe malaria risk that escapes genome-wide association studies C_LIO_LIGenome editing at the SNP demonstrates a regulatory effect on LAX1 and T cell activation C_LIO_LIEpistatic interaction between SNPs increases the risk of severe malaria C_LI In briefEpistatic interaction between common variants within a novel dual enhancer-silencer regulatory element and the LAX1 promoter variant is responsible for severe malaria susceptibility through T-cell activation.

genomics↗

bioRxiv2021

Transcriptional response in a sepsis mouse model reflects transcriptional response in sepsis patients

Mortality due to sepsis remains unacceptably high, especially for septic shock patients. Murine models have been used to better understand pathophysiology mechanisms. However, the mouse model is still under debate. Here we investigated the transcriptional response of mice injected with lipopolysaccharide (LPS) and compared it to either human cells stimulated in vitro with LPS or to blood cells of septic patients. We identified a molecular signature composed of 2331 genes with an FDR median of 0%. This molecular signature is highly enriched in regulated genes in peritoneal macrophages stimulated with LPS. There is a significant enrichment in several inflammatory signaling pathways, and in disease terms, such as pneumonia, sepsis, systemic inflammatory response syndrome, severe sepsis, an inflammatory disorder, immune suppression, and septic shock. A significant overlap between the genes up-regulated in mouse and human cells stimulated with LPS has been demonstrated. Finally, genes up-regulated in mouse cells stimulated with LPS are enriched in genes up-regulated in human cells stimulated in vitro and in septic patients, who are at high risk of death. Our results support the hypothesis of common molecular and cellular mechanisms between mouse and human sepsis.

genomics↗