Biology subjects

Couturier, C.

Publications and source records attributed to Couturier, C..

3 recordsLinked to original sources

bioRxiv2021

Single-cell Multiomics Reveals Clonal T-cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasms (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

immunology↗

bioRxiv2020

Maternal vitamin D deficiency impairs heart formation in mouse offspring through a change in 3D-chromatin structure

The origins of congenital heart diseases, the most common congenital diseases are still largely unknown. Environmental factors are now emerging as major causes of these diseases. Vitamin D deficiency has become a public health burden, notably for childbearing age, pregnant and breastfeeding women. Since maternal 25-hydroxyvitamin D (25(OH)D) determined fetal and neonatal 25(OH)D status, foetuses exposed to insufficient levels of vitamin D, may feature developmental defects. Herein, we investigated the effects of maternal vitamin D deficiency on cardiovascular defects in early and later life of offsprings in two generations as well as the molecular mechanisms underlying vitamin D effect. Eight weeks before and during pregnancy, C57BL/6JRj female mice received a sufficient or vitamin D deficient diet ((1.0 IU/g in control vs 0.0 IU/g in Vitamin D Deficient (VDD) group). E16.5 Embryos of maternal VDD diet featured hypertrophic heart revealed by a thicker left ventricular (LV) wall and septum. RNAseq analysis of LV revealed 1555 transcripts differentially expressed in the VDD group and among them cardiac transcription factors and constitutive cardiac genes (tbx5, gata4, myl2). Anti-Vitamin D receptor (VDR) Chip-seq from chromatin of E16.5 LV uncovered different targeting of tbx5 and tbx3 loci by VDR in the VDD vs control embryos. Anti-CTCF ChIP-loop experiments focusing on the Tbx3 and Tbx5 loci uncovered a change in the Topology Associated Domains associated with these loci. Echocardiography of 2-months-old VDD offspring revealed a significantly thicker left ventricle and increased fractional shortening while 6-months-old mice featured cardiac decompensation and in turn failing LV. Maternal vitamin D deficiency severely affects heart formation following a change in chromatin conformation on cardiac gene loci and impacts function of adult hearts in two generations. These defects are likely to be at the origin of cardiovascular diseases in the adulthood.

developmental biology↗

bioRxiv2019

A standardized gnotobiotic mouse model harboring a minimal 15-member mouse gut microbiota recapitulates SOPF phenotype

Mus musculus is the classic mammalian model for biomedical research. Despite global efforts to standardize breeding and experimental procedures, the undefined composition and interindividual diversity of the microbiota of laboratory mice remains a limitation. In an attempt to standardize the gut microbiome in preclinical mouse studies, we developed a simplified mouse microbiota composed of 15 strains from 7 of the 20 most prevalent bacterial families representative of the fecal microbiota of C57BL/6J Specific (and Opportunistic) Pathogen-Free (SPF/SOPF) animals and derived a new standardized gnotobiotic mouse model called GM15. GM15 recapitulates extensively the functionalities found in the C57BL/6J SOPF microbiota metagenome, and GM15 animals are phenotypically similar to SOPF or SPF animals in two different facilities. They are also less sensitive to the deleterious effects of post-weaning malnutrition. The GM15 model provides increased reproducibility and robustness of preclinical studies by limiting the confounding effect of fluctuation in microbiota composition, and offers new opportunities for research focused on how the microbiota shapes host physiology in health and disease.

microbiology↗