SysMics

SysMics (Systems Medicine based on Genomics) is a cluster in genomics, labeled by NExT I-SITE and based on the genomics and bioinformatics core facility GenoBiRD.

SysMics aims to unite the Nantes scientific community around a common goal: to anticipate the emergence of systems medicine through the development of high throughput sequencing approaches. Systems medicine is becoming a new public health standard in developed countries. This medicine is oriented towards the implementation of prevention strategies adapted to individual profiles, in order to limit adverse events in patients with chronic pathologies.

The missions of the cluster SysMics are:

• To consolidate the network in the fields of genomics and bioinformatics.
• To facilitate clinical investigations based on genome sequencing of patient populations, single cell genomics profiling and metagenomic analysis of microbiome.
• To combine genomic approaches in the context of pilot projects in immunology, oncology and physiopathology of cardiovascular, metabolic, respiratory and neuro-digestive diseases in order to build patient individual profiles.

SysMics gathers the groups conducting cutting-edge translational research in Nantes. It fosters the implementation of systems medicine, a new holistic approach of medicine.

 

• Institut du Thorax
• Center for Research in Transplantation and Translational Immunology (CR2TI)
• Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (CRCI2NA)
• Institut des maladies de l’appareil digestif (IMAD): PhAN, TENS et CIC IMAD
• Translational Research in Gene Therapy (TaRGeT)
• Laboratoire des Sciences du Numérique de Nantes (LS2N)
• CHU de Nantes
• Biofortis
• Regenerative Medicine and Skeleton (RMeS)
• Immunologie et Nouveaux Concepts en Immunothérapie (INCIT)

News

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• Jean-Baptiste Dupont (Target) - WP2: Characterization of gene expression in muscle organoids using single-cell Parse technology
• Victor Gourain (CR2TI) - WP3: Adapting the 3'SRP technique to capture prokaryotic RNAs from bronchoalveolar lavage samples. Exploration of interactions between immune cells, the microbiome and the pathogen causing infection

• Catherine Michel (PhAN) and Samuel Chaffron (LS2N) : Development of bioinformatics tools for targeted profiling of neuromediator production in publicly available infant stool metagenomic data.
• Sophie Limou (CR2TI), Gilles Blancho (CHU), Géraldine Jean (LS2N) and Mathieu (Ribatet (LMJL) : Integration of multi-omics data in renal transplantation and application of machine learning methods to create a composite diagnostic and predictive score from clinical factors and non-invasive blood markers.
• Jérôme Jullien (CR2TI) and Marion Estelle (INCIT) : Integration of ChIP-seq and bulk RNA-seq data to discriminate the different phases of the tolerance and entrainment process during epigenetic reprogramming of macrophages during exposure to Mycobacterium ligand (Buruli Ulcer).
• Maxime Mahé (TENS) and Laurent David (CR2TI) : Implementation of a cellular deconvolution tool for bulk RNA-Seq (3'SRP) data from human embryos and intestines to predict cellular heterogeneity in bulk sequencing samples.

Projects / Actions

SysMics supports cluster members by:

• participating in the organization of scientific events (conferences, seminars, etc.).
• supporting students and research projects through the awarding of SysMics GRANT scholarships.
• acting as a catalyst for the development of new approaches in genomics by collecting needs, identifying the scientific and technological locks (surveys, interviews, etc.) and supporting R&D through the SysMics AAP call.

The cluster participates in major structuring projects via technological platforms:

• The bioinformatics platform BiRD participates in the MuDiS4LS project supported by the IFB, which aims to create shared digital workspaces for life sciences.
• BiRD also participates in the management of the regional computing center GLiCID (Groupe Ligérien en Calcul Intensif Distribué).

Finally, SysMics federates research and development efforts of the partners via:

• collaborative tools like GitLab. The objective is to standardize the analyzes thanks to robust, referenced and published pipelines.
• monthly bioinformatics meetings in its collaborative space (Room 634, IRS UN).

SysMics in 1 minute:

The accessibility to Whole Genome Sequencing (WGS) has been facilitated by the purchase of an Illumina NovaSeq 6000 sequencer by the GenoA platform as well as a set of measures to lower WGS cost.

Sysmics contributed, with team I of the institut du thorax, to the development of a new sequencing method , the Low-Pass Whole Genome Sequencing (LP-WGS), allowing the genetic profiling at a reduced cost. Low-coverage sequencing is used in a research program on the genetics of intracranial aneurysms and will soon be applied to other biomedical projects.

A focus is also on WGS in oncology, in particular by the ICAGEN team of the CRCI2NA as part of the study of oncogenic alterations and clonal evolution in multiple myeloma. In parallel, the ICAGEN team is testing new technologies allowing deeper sequencing at a reduced cost. Finally, researchers are developing a multi-omics approach integrating single-cell RNA-Seq and ATAC-Seq data in order to reconstruct the molecular evolution of the tumor and understand the emergence of resistant clones.

Access to epigenetic data has become essential for the annotation of WGS and in particular for the functional characterization of non-coding regions and associated mutations. Epigenetic data are also key in the integration of gene expression data.

SysMics supported pilot projects including those led by Julien Barc from the Institut du thorax on the functional annotation of non-coding regions in patients with Brugada syndrome, a genetic disease responsible for heart arrhythmia. For that purpose, the ATAC-Seq and Cut&Run techniques were developed and validated in collaboration with the GenoA genomics platform and the bioinformatics pipelines were implemented with the help of BiRD and are now available for the community.

A growing need has been expressed in the Nantes scientific community for Single Cell Sequencing (SCS). In order to meet this demand, GenoA and the CRCI2NA have jointly acquired a Chromium controller (10x Genomics) accessible via Cytocell or GenoA platform.

The partner laboratories took advantage of SysMics' impetus:

• Jéremie Poschmann's team from CR2TI set up single cell sequencing pilot projects thanks to Chromium availability. Since then, the CR2TI has been equipped with its own equipment and benefits from the accessibility to NovaSeq sequencer in order to carry out its research projects on the alterations of immune cells after acute inflammatory stress.
• The team of Stéphane Minvielle and Eric Letouzé from CRCI2NA uses NovaSeq sequencer to conduct ancillary genomic studies related to multicenter clinical trials in multiple myeloma. Their studies include the characterization of myeloma cells from patients collected prospectively at different stages of the disease and the characterization of the tumor immune microenvironment by Single-Cell RNA-Seq and/or ATAC-Seq. The expertise acquired was transmitted to other teams at CRCI2NA and applied to additional oncology studies.

SysMics supported a project conducted by the institut du thorax that was based on the use of stem cells reprogrammed into cardiac cells or hepatocytes. This project led to the molecular characterization of the cell lines and the identification of the cell populations obtained after hepatic differentiation of human iPSCs in 2D versus 3D models.

In parallel, Jean-Baptiste Dupont's team from the TaRGeT laboratory is currently setting up SCS approaches using combinatorial indexing in collaboration with the GenoA platform. The long-term goal is to propose an alternative technology to analyze numerous samples simultaneously at a lower cost.

Microbiome consists of the community of microorganisms (bacteria, fungi, etc.) found in a certain environment. Microbiota corresponds to all living organisms forming a microbiome. These organisms play essential roles by supporting major functions in their specific habitat. In humans, microbiota is crucial and influences Health at all stages of life, in particular by protecting from pathogens and by facilitating the digestion through the transformation of many substrates into metabolites.

For several years, researchers from Nantes have been contributing to the establishment of a real ecosystem for the development of innovative projects on microbiome. Today, that field is booming in the regional scientific community.

Thanks to the support of SysMics, two methods used for the microbiome analysis have been developed and are currently available on the GenoA platform:

• The targeted sequencing method of the V3-V4 regions of the 16S ribosomal DNA gene for the characterization of the diversity and composition of bacterial profiles in samples.
• The “Shotgun” metagenomic sequencing method to identify all the microorganisms present in a sample and their functions.

In order to process the data obtained by sequencing, dedicated bioinformatics tools have been developed by the LS2N ComBi team and by the BiRD platform:

• A workflow for 16S sequencing analysis was developed in collaboration with TENS and validated on several projects, in particular within the framework of the regional Mibiogate project. This pipeline called MicroSysMics is available on BiRD's GitLab.
• A workflow for shotgun metagenomic sequencing analysis by reference-based approach was developed in collaboration with the team of Emmanuel Montassier and Quentin Le Bastard: BioBakery.
• A workflow for de novo metagenomic assembly was implemented: MAGNETO.

The 16S metabarcoding approach has been used in several preclinical and translational projects, in particular from the TENS laboratory:

• A recent study used the 16S sequencing to characterize the impact of prebiotics administered to the mother during gestation on the susceptibility of the offspring to develop colitis (Lê et al. 2023).
• A study in patients with irritable bowel syndrome receiving probiotics found changes in the gut microbiota predictive of response to treatment (Marchix et al. 2023).
• Among on-going studies, one project aims to characterize the composition of the microbiota in patients with Spina Bifida (Charlène Brochard).
• Guillaume Chapelet's team investigates the correlation between variations in the microbiota of elderly people living in nursing homes and neurodegenerative diseases.

The Shotgun sequencing technique was used by Laureline Berthelot's team from CR2TI during a pilot project supported by SysMics on the salivary microbiota of patients with multiple sclerosis. The investigators confirmed the dysbiosis of the oral microbiota in these patients with a modification of the bacterial metabolic pathways and an impact of corticosteroid treatment on the viral flora.

The implementation of systems medicine requires to face major challenges. Before considering using multi-omics data in the care pathways, issues related to the integration of heterogeneous health data and to the use of these types of data need to be addressed.

To meet these challenges, SysMics supports projects regarding:

• Data integration from a set of heterogeneous sources. This involves the development of new computer models, such as the modeling of a patient's metabolism in the Humess project (BioGenouest) or the use of graph data structures. The cluster IBD-NExT financed the internship of a Master's student to create a knowledge graph in order to discover biomarkers of Inflammatory bowel diseases (IBD).
• Access and use of Health data. Actions are being taken to ease the access and use of data with the help of la clinique des données and the clusters HéMA-NExT and DELPHI. More concretely, a student developed a model of automatic language processing to extract information from clinical reports of patients with malignant hemopathies. Several PhD projects have also been financially supported in connection with the project AiBy4.

• BiRD bioinformatics workshops. The platform BiRD organizes regular training courses in bioinformatics. For more information, please visit BiRD website: https://pf-bird.univ-nantes.fr/training

Project manager : Richard REDON
Coordinators : Audrey BIHOUEE et Marine CORNEC
contact-sysmics@univ-nantes.fr

Winner of the “Integrative Research Cluster (IRC)” call, SysMics received 235 k€ for 4 years (2018-2022). The project is extended until the end of 2024 with an additional amount of 150 k€. Led by NExT through the government support managed by the French National Research Agency under the "France 2030" investment plan, the project benefits from financial support from Région Pays de la Loire and Nantes Métropole.

The project leader who received support from SysMics is committed to thank the cluster SysMics in scientific publications as followed:
“This work was carried out with the help of the cluster SysMics. It benefited from the government support managed by the French National Research Agency under the France 2030 investment plan and from the financial support of the Région Pays de la Loire and Nantes Métropole”.

The project beneficiaries must touch upon SysMics support during media interviews and inform NExT team in advance.

Publications

Rare coding variants in CTSO, a potential new actor of arterial remodeling, are associated to familial intracranial aneurysm
Freneau et al. Preprint. MedRxiv. 2023. https://doi.org/10.1101/2023.01.31.23285168

Maternal prebiotic supplementation impacts colitis development in offspring mice.
Lê et al. Front Nutr. 2023. https://doi.org/10.3389/fnut.2022.988529

A new 165-SNP low-density lipoprotein cholesterol polygenic risk score based on next generation sequencing outperforms previously published scores in routine diagnostics of familial hypercholesterolemia.
Vanhoye et al. Translational Research. 2023. https://doi.org/10.1016/j.trsl.2022.12.002

KiT-GENIE, the French genetic biobank of kidney transplantation.
Ba et al. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01294-z

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.
Chen et al. European Heart Journal. https://doi.org/10.1093/eurheartj/ehad142

LDL lowering effect of PCSK9 inhibition is reduced in women.
Myasoedova et al. European Heart Journal - Cardiovascular Pharmacotherapy. https://doi.org/10.1093/ehjcvp/pvad009

Deciphering Transcriptional Networks during Human Cardiac Development.
Canac et al. Cells 2022. https://doi.org/10.3390/cells11233915

Human gut microbiota-reactive DP8α regulatory T cells, signature and related emerging functions.
Jotereau et al. Front Immunol. 2022 https://doi.org/10.3389/fimmu.2022.1026994

Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form‐associated genes provides new insights for molecular diagnosis and clinical management.
Goudal et al. Hum Mutat. 2022. https://doi.org/10.1002/humu.24436

Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis.
Morel et al. J Pers Med 2022. https://doi.org/10.3390/jpm12091410

Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model.
Delwarde et al. Cardiovasc Res 2022. https://doi.org/10.1093/cvr/cvac136

MAGNETO: An Automated Workflow for Genome-Resolved Metagenomics.
Churcheward et al. mSystems 2022. https://doi.org/10.1128/msystems.00432-22

EDAM, the life-science ontology for data analysis and management.
Lamothe et al. Zenodo 2022. https://doi.org/10.5281/zenodo.6769072

Diversity and ecological footprint of Global Ocean RNA viruses.
Dominguez-Huerta et al. Science. 2022. https://doi.org/10.1126/science.abn6358

Oral exposure to bisphenol A exacerbates allergic inflammation in a mouse model of food allergy.
Misme‐aucouturier et al. Toxicology 2022. https://doi.org/10.1016/j.tox.2022.153188

Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.
Barc et al. Nature Genetics 2022. https://doi.org/10.1038/s41588-021-01007-6

Cryptic and abundant marine viruses at the evolutionary origins of Earth’s RNA virome.
Zayed et al. Science. 2022. https://doi.org/10.1126/science.abm5847

Generation of human induced pluripotent stem cell lines from four unrelated healthy control donors carrying European genetic background.
Girardeau et al. Stem Cell Res. 2021. https://doi.org/10.1016/j.scr.2021.102647

Generation of CD34+CD43+ Hematopoietic Progenitors to Induce Thymocytes from Human Pluripotent Stem Cells.
Flippe et al. Cells 2022. https://doi.org/10.3390/cells11244046

The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition.
Decombis et al. Haematologica 2022. https://doi.org/10.3324/haematol.2021.279800

CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy.
Drouin et al. Sci Adv. 2022. https://doi.org/10.1126/sciadv.abo7621

Patients with severe multiple sclerosis exhibit functionally altered CD8+ regulatory T cells.
Benallegue et al. Neurol Neuroimmunol Neuroinflamm. 2022. https://doi.org/10.1212/NXI.0000000000200016

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile.
Rimbert et al. Arterioscler Thromb Vasc Biol. 2022. https://doi.org/10.1161/ATVBAHA.122.317514

Modelling the effects of antimicrobial metaphylaxis and pen size on bovine respiratory disease in high and low risk fattening cattle.
Picault et al. Vet Res. 2022. https://doi.org/10.1186/s13567-022-01094-1

Targeting of MCL-1 in breast cancer-associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties.
Bonneaud et al. Cell Death Dis. 2022. https://doi.org/10.1038/s41419-022-05214-9
 
Quantification of APOBEC3 Mutation Rates Affecting the VP1 Gene of BK Polyomavirus In Vivo.
McIlroy et al. Viruses. 2022. https://doi.org/10.3390/v14092077

Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma.
André-Grégoire et al. iScience. 2022. https://doi.org/10.1016/j.isci.2022.105118

Distinct role of mitochondrial function and protein kinase C in intimal and medial calcification in vitro.
Heuschkel et al. Front Cardiovasc Med. 2022. https://doi.org/10.3389/fcvm.2022.959457

The African swine fever modelling challenge: Model comparison and lessons learnt.
Ezanno et al. Epidemics. 2022. https://doi.org/10.1016/j.epidem.2022.100615

Identification of a Gain-of-Function LIPC Variant as a Novel Cause of Familial Combined Hypocholesterolemia. Circulation.
Dijk et al. Circulation 2022. https://doi.org/10.1161/CIRCULATIONAHA.121.057978

Monocyte Signature Associated with Herpes Simplex Virus Reactivation and Neurological Recovery after Brain Injury.
Chaumette et al. Am J Respir Crit Care Med. 2022. https://doi.org/10.1164/rccm.202110-2324OC

Molecular Signature of 18F-FDG PET Biomarkers in Newly Diagnosed Multiple Myeloma Patients: A Genome-Wide Transcriptome Analysis from the CASSIOPET Study.
Alberge et al. J Nucl Med. 2022. https://doi.org/10.2967/jnumed.121.262884

The DCMU Herbicide Shapes T-cell Functions By Modulating Micro-RNA Expression Profiles.
Autin et al. Front Immunol. 2022. https://doi.org/10.3389/fimmu.2022.925241

Moment Estimators of Relatedness From Low-Depth Whole-Genome Sequencing Data.
Herzig et al. BMC Bioinformatics 2022. https://doi.org/10.1186/s12859-022-04795-8

Contribution of genome-scale metabolic modelling to niche theory.
Régimbeau et al. Ecol Lett. 2022. https://doi.org/10.1111/ele.13954

Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression.
Dupas et al. Int J Mol Sci. 2022. https://doi.org/10.3390/ijms23126430

A Histone Deacetylase Inhibitor Induces Acetyl-CoA Depletion Leading to Lethal Metabolic Stress in RAS-Pathway Activated.
Basseville et al. Cancers (Basel) 2022. https://doi.org/10.3390/cancers14112643

Human and insect cell-produced rAAVs show differences in genome heterogeneity.
Tam Tran et al. Human Gene Therapy 2022. https://doi.org/10.1089/hum.2022.050

Generation of human induced pluripotent stem cell lines from three patients affected by Catecholaminergic Polymorphic ventricular tachycardia (CPVT) carrying heterozygous mutations in RYR2 gene.
Cimarosti et al. Stem Cell Research 2022. https://doi.org/10.1016/j.scr.2022.102688

Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.
Küry et al. Am J Hum Genet. 2022. https://doi.org/10.1016/j.ajhg.2021.12.011

Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes.
Combot et al. Cell Rep. 2022. https://doi.org/10.1016/j.celrep.2021.110213

Latent representation of single-cell transcriptomes enables algebraic operations on cellular phenotypes.
Bhattacharya et al. BioRxiv. https://doi.org/10.1101/2022.12.28.522060

Combined in vivo and in situ genome-resolved metagenomics reveals novel symbiotic nitrogen fixing interactions between non-cyanobacterial diazotrophs and microalgae.
Chandola et al. BioRxiv. https://doi.org/10.1101/2022.08.25.505241

PhaeoEpiView: An epigenome browser of the newly assembled genome of the model diatom Phaeodactylum tricornutum.
Wu et al. BioRxiv. https://doi.org/10.1101/2022.07.29.502047

Pyruvate carboxylation identifies Glioblastoma Stem-like Cells opening new metabolic strategy to prevent tumor recurrence.
Renoult et al. BioRxiv. https://doi.org/10.1101/2022.07.18.500427

Disentangling temporal associations in marine microbial networks.
Deutschmann et al. bioRxiv. https://doi.org/10.1101/2021.07.13.452187

Genetic population structure across Brittany and the downstream Loire basin provides new insights on the demographic history of Western Europe.
Alves et al. BioRxiv. https://doi.org/10.1101/2022.02.03.478491

ARHGEF18 participates in Endothelial Cell Mechano-sensitivity in Response to Flow.
Batta et al. BioRxiv. https://doi.org/10.1101/2022.09.10.507283