Biology subjects

Fantin, A.

Publications and source records attributed to Fantin, A..

4 recordsLinked to original sources

bioRxiv2023

BulkECexplorer: a bulk RNAseq compendium of five endothelial subtypes that predicts whether genes are active or leaky

Transcriptomic data obtained by single cell (sc) RNAseq or bulk RNAseq can be mined to understand the molecular activity of cell types. Yet, lowly expressed but functional genes may remain undetected in RNAseq experiments for technical reasons, such as insufficient read depth or gene drop out in scRNAseq assays. By contrast, bulk RNAseq assays may detect lowly expressed mRNA transcripts thought to be the biologically irrelevant products of leaky transcription. To more accurately represent a cells functional transcriptome, we propose compiling many bulk RNAseq datasets into a compendium and applying established classification models to predict whether the detected genes are likely active or leaky in that cell type. Here, we have created such a compendium for vascular endothelial cells from several mouse and human organs, termed the BulkECexplorer.

bioinformatics↗

bioRxiv2023

A refined single cell landscape of haematopoiesis in the mouse foetal liver

During prenatal life, the foetal liver is colonised by several waves of haematopoietic stem and progenitor cells (HSPCs) to act as the main haematopoietic organ. Single cell (sc) RNA-seq has been used to identify foetal liver cell types via their transcriptomic signature and to compare gene expression pattern as haematopoietic development proceeds. To obtain a refined single cell landscape of haematopoiesis in the foetal liver, we have generated a novel scRNA-seq dataset from whole mouse E12.5 liver that includes a larger number of cells than prior datasets at this stage and was obtained without cell type preselection to include all liver cell populations. We combined mining of this dataset with that of previously published datasets at other developmental stages to follow transcriptional dynamics as well as cell cycle state of developing haematopoietic lineages. Our findings corroborate several prior reports on the timing of liver colonisation by HSPCs and the emergence of differentiated lineages and provide further molecular characterisation of each cell population. Extending these findings, we demonstrate the existence of a foetal intermediate haemoglobin profile in the mouse, similar to that previously identified in humans, and a previously unidentified population of primitive erythroid cells in the foetal liver.

developmental biology↗

bioRxiv2022

Metformin antiproliferative activity is exclusively mediated by the membrane functional expression of the Chloride Intracellular Channel 1 in glioblastoma stem cells

Metformin is the first-line drug for type-2 diabetes. Retrospective analyses, based on diabetic patients clinical data, demonstrate that daily assumption of metformin reduces the incidence of several kinds of solid tumors. Even though it is widely agreed that metformin must be internalized to accomplish its pharmacological activity, direct evidence about metformin membrane permeability and/or the presence of a specific membrane receptor in cancer cells is still missing. Here, we show that the transmembrane form of Chloride Intracellular Channel 1 (tmCLIC1) works as a privileged metformin receptor in glioblastoma stem-like cells. We found that metformin impairs tmCLIC1 activity by a specific binding coordinated by arginine 29. Its mutation, preventing metformin to bind and block tmCLIC1, abolishes the biguanide inhibition of glioblastoma cell proliferation in 2D and 3D models and metformin dependent effect on mitochondrial respiration. In addition, we demonstrate the direct binding between the drug and its target, and by in vivo experiments on zebrafish embryos and mice orthotopically engrafted with glioblastoma cells and treated with metformin, we prove that metformin binding to tmCLIC1 is crucial for metformin antineoplastic effect. Considering tmCLIC1s contribution to glioblastoma progression, the present work provides the fundaments for future development of strategies aimed at improving metformin-tmCLIC1 interaction to further increase metformin therapeutic potential.

cancer biology↗

bioRxiv2021

KIT is required for fetal liver erythropoiesis but dispensable for angiogenesis

Blood vessels are fundamental to sustain organ growth and tissue metabolism. In the mouse embryo, endothelial cell (EC) progenitors almost concomitantly give rise to the first blood vessels in the yolk sac and the large vessels of the embryo proper. Thereafter, the vascular network expands by angiogenesis to vascularize developing organs such as the brain. Although the first blood cells form in the yolk sac before blood vessels have assembled, consecutive waves of hematopoietic progenitors subsequently bud from hemogenic endothelium located within the wall of yolk sac and large intraembryonic vessels in a process termed endothelial to hematopoietic transition (endoHT). The receptor tyrosine kinase KIT is required for late embryonic erythropoiesis, but KIT is also expressed earlier in the hemogenic endothelium, in hematopoietic progenitors that arise via endoHT from hemogenic endothelium and non-hemogenic ECs, such as in the brain. However, it remains unclear whether KIT has essential roles in early hematopoiesis or even blood vessel growth. Here, we have combined transcriptomic analysis to delineate Kit expression with the analysis of knockout mice to show that KIT is expressed during but dispensable for yolk sac endoHT or brain angiogenesis but required for transient definitive erythropoiesis in the fetal liver.

developmental biology↗