Biology subjects

Blanc, V.

Publications and source records attributed to Blanc, V..

5 recordsLinked to original sources

bioRxiv2026

mRNA editing of the Alzheimer's risk gene APOE

Variants in the human APOE gene govern the risk of Alzheimer's disease and other disorders. Three major APOE variants in humans reflect C to T replacements at two positions in a single exon: an upstream variant (AE4 site) that differs between the ancestral APOE epsilon 4 allele (APOE4) (C) and human-specific APOE2/E3 (T), and a downstream variant (AE2 site) that differentiates APOE3/E4 (C) from APOE2 (T). It has long been assumed that APOE allelotypes are genomically encoded, but here we report that multiple individuals express brain APOE C or U/T variant transcripts that differ from genomically templated versions. We demonstrate up to 10% C to U, or U to C nucleotide replacement at AE4 and AE2, but not at other sites, and with no corresponding changes in genomic DNA. Single-cell transcriptomic datasets from brain microglia revealed sporadic (up to ~8%) C to U replacement at AE2. We found 0.4 to 1.6% of brain transcripts in human APOE knock-in mice harbor selective C to U changes at either AE4 or AE2 sites. Transfection of HepG2 or Huh7 cells with either mouse or human APOBEC1 led to efficient (>90%) C to U editing of APOE4 mRNA at the AE4 but not AE2 site, with lower (<10%) C to T editing of genomic DNA at the AE4 site by mouse, but not human, APOBEC1. Furthermore, interrogation of proteomic datasets revealed up to 4% of non-genomically encoded APOE peptides in human plasma, indicating that the edited APOE transcripts are functional in vivo. These data suggest that APOE mRNA is subject to RNA editing that interconverts the different allelic forms of APOE.

genetics↗

bioRxiv2024

Spatial transcriptomics unveils immune cellular ecosystems associated with patient survival in diffuse large B-cell lymphoma

Diffuse Large B-cell Lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkins lymphoma for which current therapeutic strategies remain insufficient. The diffuse nature of DLBCL, lacking distinct tissue structures, represents a challenge to elucidate the cellular organization and interactions within the tumor microenvironment (TME). In this study, we applied spatial transcriptomics to identify spatially-resolved gene expression profiles in 10 DLBCL tissue samples, identifying distinct immune cell infiltration and colocalization patterns. These profiles were classified into six cellular ecosystems (Cell-Eco) that differ in cellular composition, functional patterns, and neighborhood characteristics. The spatially-resolved Cell-Eco signatures provided prognostic scores that stratified patients with different overall survival rates. We also found that C1q+ tumor-associated macrophages are the primary cells interacting with malignant B cells and influencing the spatial architecture of the TME. This study provides novel biological insights into the complexity of the TME in DLBCL and highlights the potential prognostic value of its spatial organization. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/613252v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@147a46eorg.highwire.dtl.DTLVardef@7c5236org.highwire.dtl.DTLVardef@1f99506org.highwire.dtl.DTLVardef@a6d271_HPS_FORMAT_FIGEXP M_FIG C_FIG Key findingsO_LISpatial transcriptomics classifies DLBCL tissues based on immune cell infiltration and colocalization patterns. C_LIO_LIDLBCL tumor microenvironment consists of cellular ecosystems (Cell-Eco) that differ in cellular composition, transcriptomic profiles and neighborhood characteristics. C_LIO_LISpatially-resolved Cell-Eco signatures stratify patients with different overall survival. C_LIO_LIC1q+ tumor-associated macrophages primarily interact with malignant B cells and contribute to the spatial organization of the tumor microenvironment. C_LI

immunology↗

bioRxiv2021

APOBEC1 mediated C-to-U RNA editing: target sequence and trans-acting factor contribution to 177 RNA editing events in 119 murine transcripts in-vivo

Mammalian C-to-U RNA editing was described more than 30 years ago as a single nucleotide modification in APOB RNA in small intestine, later shown to be mediated by the RNA-specific cytidine deaminase APOBEC1. Reports of other examples of C-to-U RNA editing, coupled with the advent of genome-wide transcriptome sequencing, identified an expanded range of APOBEC1 targets. Here we analyze the cis-acting regulatory components of verified murine C-to-U RNA editing targets, including nearest neighbor as well as flanking sequence requirements and folding predictions. We summarize findings demonstrating the relative importance of trans-acting factors (A1CF, RBM47) acting in concert with APOBEC1. Using this information, we developed a multivariable linear regression model to predict APOBEC1 dependent C-to-U RNA editing efficiency, incorporating factors independently associated with editing frequencies based on 103 Sanger-confirmed editing sites, which accounted for 84% of the observed variance. Co-factor dominance was associated with editing frequency, with RNAs targeted by both RBM47 and A1CF observed to be edited at a lower frequency than RBM47 dominant targets. The model also predicted a composite score for available human C-to-U RNA targets, which again correlated with editing frequency.

bioinformatics↗

bioRxiv2020

Cetylpyridinium chloride-containing mouthwashes reduce in vitro SARS-CoV-2 infectivity

Oral mouthwashes decrease the infectivity of several respiratory viruses including SARS-CoV-2. However, the precise agents with antiviral activity present in these oral rinses and their exact mechanism of action remain unknown. Here we show that Cetylpyridinium chloride (CPC), a quaternary ammonium compound present in many oral mouthwashes, reduces SARS-CoV-2 infectivity by inhibiting the viral fusion step with target cells after disrupting the integrity of the viral envelope. We also found that CPC-containing mouth rinses decreased more than a thousand times the infectivity of SARS-CoV-2 in vitro, while the corresponding vehicles had no effect. This activity was effective for different SARS-CoV-2 variants, including the B.1.1.7 variant, predominant in UK, also in the presence of sterilized saliva. CPC-containing mouth rinses could therefore represent a cost-effective measure to reduce SARS-CoV-2 infectivity in saliva, aiding to reduce viral transmission from infected individuals regardless of the variants they are infected with.

microbiology↗

bioRxiv2018

Exploring Various Polygenic Risk Scores for Basal Cell Carcinoma, Cutaneous Squamous Cell Carcinoma and Melanoma in the Phenomes of the Michigan Genomics Initiative and the UK Biobank

Polygenic risk scores (PRS) are designed to serve as a single summary measure, condensing information from a large number of genetic variants associated with a disease. They have been used for stratification and prediction of disease risk. The construction of a PRS often depends on the purpose of the study, the available data/summary estimates, and the underlying genetic architecture of a disease. In this paper, we consider several choices for constructing a PRS using summary data obtained from various publicly-available sources including the UK Biobank and evaluate their abilities to predict outcomes derived from electronic health records (EHR). Weexamine the three most common skin cancer subtypes in the USA: basal cellcarcinoma, cutaneous squamous cell carcinoma, and melanoma. The genetic risk profiles of subtypes may consist of both shared and unique elements and we construct PRS to understand the common versus distinct etiology. This study is conducted using data from 30,702 unrelated, genotyped patients of recent European descent from the Michigan Genomics Initiative (MGI), a longitudinal biorepository effort within Michigan Medicine. Using these PRS for various skin cancer subtypes, we conduct a phenome-wide association study (PheWAS) within the MGI data to evaluate their association with secondary traits. PheWAS results are then replicated using population-based UK Biobank data. We develop an accompanying visual catalog called PRSweb that provides detailed PheWAS results and allows users to directly compare different PRS construction methods. The results of this study can provide guidance regarding PRS construction in future PRS-PheWAS studies using EHR data involving disease subtypes.\n\nAuthor summaryIn the study of genetically complex diseases, polygenic risk scores synthesize information from multiple genetic risk factors to provide insight into a patients risk of developing a disease based on his/her genetic profile. These risk scores can be explored in conjunction with health and disease information available in the electronic medical records. They may be associated with diseases that may be related to or precursors of the underlying disease of interest. Limited work is available guiding risk score construction when the goal is to identify associations across the medical phenome. In this paper, we compare different polygenic risk score construction methods in terms of their relationships with the medical phenome. We further propose methods for using these risk scores to decouple the shared and unique genetic profiles of related diseases and to explore related diseases shared and unique secondary associations. Leveraging and harnessing the rich data resources of the Michigan Genomics Initiative, a biorepository effort at Michigan Medicine, and the larger population-based UK Biobank study, we investigated the performance of genetic risk profiling methods for the three most common types of skin cancer: melanoma, basal cell carcinoma and squamous cell carcinoma.

genetics↗