By studying the assimilation pathways of iron and its intracellular metabolism in a model organism, the yeast Saccharomyces cerevisiae, we can address some of the fundamental problems of biology whilst considering new applications within the field of therapeutics or furthering our knowledge and understanding of the molecular bases of human pathologies.
Iron is an essential trace element for all living cells, but both excess and deficient iron intake are harmful to the cell. Iron homeostasis is therefore tightly regulated in most, if not all, living systems. In humans, diseases related to abnormalities in iron homeostasis can result either from environmental factors or from certain genetic abnormalities.
Iron is the redox center of the heme and iron-sulfur centers, which are essential cofactors in many cellular functions, including energy production and oxygen metabolism. Adequate iron intake is therefore mandatory for normal cell growth and survival. However, due to its chemical reactivity, iron can be toxic to the cell, and paradoxically, iron deficiency and iron overload have been associated with increased production of harmful reactive oxygen species (ROS).
We are studying several aspects of iron metabolism: its transport across the plasma membrane and its utilization in mitochondria, the control of the expression of genes encoding components of the iron metabolism machinery in different eukaryotic model systems. This leads us to study in parallel the control of thiol-dependent responses to oxidative stress, a condition often associated with alterations in iron homeostasis.
Our objects of study are :
– human cells, to better understand the molecular basis of a fatal neurodegenerative disease, Friedreich’s ataxia
– yeasts, S. cerevisiae as a model system, and C. albicans to better understand the role of iron as a virulence factor
– marine microalgae to better understand the mechanisms of adaptation of phytoplankton to major environmental changes: increase in temperature, increase in CO2, change in pH of the marine environment.
We are developing an original and very innovative method of metabolic labelling (SLIM-Labeling) of the different cell types that we study to analyze the quantitative variations of protein abundance in response to different biological stresses. In particular, we apply this new approach to the study of the molecular basis of the yeast/hybrid transition and the epigenetic control of this transition.
Computational biology approaches are essential for the study of the large-scale datasets we produce (transcriptomics, quantitative proteomics, phenomena), and we actively contribute to the production of new open source bioinformatics tools that can be used by the scientific community
Research project #1 (Valérie Serre)
Friedreich’s ataxia (FA) is an inherited neurodegenerative disease, due to an unstable GAA repeat located in intron 1 of the FXN gene (9q21.11) coding for frataxin. This protein plays a critical role in the biogenesis of iron-sulfur clusters and iron transport in the mitochondria. A deficiency in this mitochondrial protein leads to the progressive disruption of the central and peripheral nervous systems observed in FA. The size of the shortest allele is inversely proportional to the age of onset of the disease and the time from clinical onset to wheelchair confinement. It is positively correlated with the prevalence of cardiomyopathy.
For many years great efforts have been made to develop treatment to improve the clinical symptoms of FA. However, the development of an effective treatment remains a challenge because the pathophysiology of FA remains not fully resolved. The discovery of biomarkers in rare genetic diseases is accelerating medical research by shedding light on the pathophysiological mechanisms of the diseases. Other than measuring frataxin expression, there are currently no robust protein biomarkers known to be related to FA severity or progression. Furthermore, current knowledge of FA offers various therapeutic approaches under investigation, but there are no reliable biomarkers to assess treatment efficacy.
Our project aims to accelerate the discovery of therapeutic targets using a high-throughput quantitative proteomics approach, with the goal of identifying biomarkers of interest from FA patient plasma samples.
The raw data from the quantitative proteomics are analyzed using statistical and bioinformatics tools according to a pipeline that we have developed. This analysis pipeline uses scripts in R language included in a R Markdown file, allowing to generate detailed, commented, and reproducible analysis reports, as well as the use of open source software platforms. All these bioinformatics analyses follow the general principles of reproducible science with FAIR (Findable, Accessible, Interoperable and Reproducible). The validation of these potential biomarkers can be easily performed by Western blot or ELISA tests in routine.
This work, carried out in close collaboration with the proteomics platform of the Institut Jacques Monod and the Institut du Cerveau (Paris), will hopefully lead to the identification of specific protein markers for the follow-up of AF patients and to the implementation of targeted and efficient therapeutic strategies.
Projet de recherche #2 (Françoise Auchère)
Research project #2 (Françoise Auchère)
Regulation of the cellular redox state and adaptive response of the opportunistic pathogen Candida albicans.
Candida albicans is a fungus normally present in oral cavities, skin, vaginal and digestive mucosa. It is a dimorphic yeast that can be found as a yeast or in filamentous form, and the adaptability of this opportunistic pathogen to different environmental conditions plays an important role in the virulence phenomenon.
We are interested in the adaptive metabolic response of C. albicans in the presence of different carbon sources on both yeast and filamentous forms. Using combined biochemical and microbiological approaches, as well as global proteomic approaches, we are investigating the different metabolic adaptations associated with the filamentation process, and the changes in mitochondrial function that may allow adaptation during host tissue invasion.
Research project #3 (Emmanuel Lesuisse, deceased in August 2021; project continued in collaboration with Robert Sutack, Biocev Prague)
The bioavailability of metals, and iron in particular, is highly impacted by the modification of marine ecosystems due to human activities (increased CO2 levels and ocean acidification). Surprisingly, phytoplankton metallomes/metalloproteomes are poorly characterized, and predictions on the evolution of iron bioavailability are contradictory. Our goal is to address this data gap and model the effects of ocean acidification on the biogeochemical cycling of iron. A large pool of iron is associated with the surface of different phytoplankton species. We study this iron pool as a function of pCO2 using biochemical and biophysical techniques (sorption studies and synchrotron-based techniques). We characterize the metallomes of species grown under different pCO2 in the presence of different metals and study the effects of metals and pCO2 on interspecific competition. The pH response is also studied in the model alga Ostreococcus tauri.
Research project #4 (Jean-Michel Camadro)
New metabolic labeling method for the quantification of (intact) protein abundance variations at the proteome scale.
Our experimental approaches rely heavily on quantitative “label free” proteomic analyses. In collaboration with the engineers of the IJM proteomics platform, we have developed a new analysis method, the “SLIM-labeling”, which uses the ability of most living systems to synthesize the non-essential amino acids that make up proteins from a single carbon source, such as glucose.
SLIM-Labeling aims to increase the level of the light (12C) carbon isotope in proteins, which significantly improves the accuracy of protein mass measurement, and allows the development of novel quantification methods.
We apply this approach to the study of ribosomal proteins abundance in the yeast S. cerevisiae, to the study of the yeast/hyphal transition in C. albicans, and its epigenetic control, to the development of the nematode C. elegans (collaboration with Team Dumont, IJM) and to the labeling of human cells in culture (collaboration with Team Ladoux/ Mège, IJM)
Transversal research project (Pierre Poulain)
Development of methods and tools for the exploration, analysis and visualization of biological data, particularly in proteomics.
Among these methods and tools developped in the group, we can mention :
– The AutoClassWrapper Python library and the AutoClassWeb web service for unsupervised Bayesian classification of omics experimental results.
– The bSLIM method for quantitative mass spectrometry analysis by metabolic labeling with a light isotope.
– Finally, the collaborative project Minomics aims at multi-omics analysis of biological networks by a holistic approach.
Pierre Poulain is also a Software Heritage Ambassador to promote the archiving of open source scientific software.
Group Leader :
Téléphone : +33 (0)157278029
- Françoise AUCHERE (Enseignant chercheur)
Téléphone : +33 (0)157278028
- Thibaut POINSIGNON (Doctorant)
- Pierre POULAIN (Enseignant chercheur)
Téléphone : +33 (0)157278028
- Valérie SERRE (Enseignant chercheur)
Téléphone : +33 (0)157278028
- Robert SUTAK (Biocev, Prague, visiting scientist)
- Mohammed OUSSAREN (M2 Bioinformatique)
- Emmanuel LESUISSE (Research director)
1: Functional networks of co-expressed genes to explore iron homeostasis processes in the pathogenic yeast Candida glabrata.
Denecker T, Zhou Li Y, Fairhead C, Budin K, Camadro JM, Bolotin-Fukuhara M, Angoulvant A, Lelandais G.
NAR Genom Bioinform. 2020 Apr 20;2(2):lqaa027. doi: 10.1093/nargab/lqaa027.
PMID: 33575583; PMCID: PMC7671338.
2: Novel Insights into Quantitative Proteomics from an Innovative Bottom-Up Simple Light Isotope Metabolic (bSLIM) Labeling Data Processing Strategy.
Sénécaut N, Alves G, Weisser H, Lignières L, Terrier S, Yang-Crosson L, Poulain P, Lelandais G, Yu YK, Camadro JM.
J Proteome Res. 2021 Mar 5;20(3):1476-1487.
doi: 10.1021/acs.jproteome.0c00478. Epub 2021 Feb 11.
PMID: 33573382; PMCID: PMC8459934.
3: Iron Uptake Mechanisms in Marine Phytoplankton.
Sutak R, Camadro JM, Lesuisse E.
Front Microbiol. 2020 Nov 5;11:566691. doi:10.3389/fmicb.2020.566691.
PMID: 33250865; PMCID: PMC7676907.
4: The adaptive response to iron involves changes in energetic strategies in the pathogen Candida albicans.
Duval C, Macabiou C, Garcia C, Lesuisse E, Camadro JM, Auchère F.
Microbiologyopen. 2020 Feb;9(2):e970. doi:10.1002/mbo3.970. Epub 2019 Dec 1.
PMID: 31788966; PMCID: PMC7002100.
5: Redox modifications of cysteine-containing proteins, cell cycle arrest and translation inhibition: Involvement in vitamin C-induced breast cancer cell death.
El Banna N, Hatem E, Heneman-Masurel A, Léger T, Baïlle D, Vernis L, Garcia C, Martineau S, Dupuy C, Vagner S, Camadro JM, Huang ME.
Redox Biol. 2019 Sep;26:101290. doi: 10.1016/j.redox.2019.101290. Epub 2019 Aug 2.
PMID: 31412312; PMCID: PMC6831881.
6: NDUFS6 related Leigh syndrome: a case report and review of the literature.
Rouzier C, Chaussenot A, Fragaki K, Serre V, Ait-El-Mkadem S, Richelme C, Paquis-Flucklinger V, Bannwarth S.
J Hum Genet. 2019 Jul;64(7):637-645. doi: 10.1038/s10038-019-0594-4. Epub 2019 Apr 4.
7: N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer’s disease and vascular dementia.
Bossenmeyer-Pourié C, Smith AD, Lehmann S, Deramecourt V, Sablonnière B, Camadro JM, Pourié G, Kerek R, Helle D, Umoret R, Guéant-Rodriguez RM, Rigau V, Gabelle A, Sequeira JM, Quadros EV, Daval JL, Guéant JL.
J Pathol. 2019 Jul;248(3):291-303. doi: 10.1002/path.5254. Epub 2019 Mar 19.
8: Quantitative proteomics in Friedreich’s ataxia B-lymphocytes: A valuable approach to decipher the biochemical events responsible for pathogenesis.
Télot L, Rousseau E, Lesuisse E, Garcia C, Morlet B, Léger T, Camadro JM, Serre V.
Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt
A):997-1009. doi: 10.1016/j.bbadis.2018.01.010. Epub 2018 Jan 9.
Nicolas Sénécaut (Jean-Michel Camadro, DT, Gaëlle Lelandais co-DT)
Nouvelles approches de quantification des variations du protéome au niveau des protéines intactes : analyses expérimentales et computationnelles
Katerina Zeniskova (Robert Sutak, DT, Jean-Michel Camadro external supervisor)
Effect of various stress factors on mitochondrial processes of pathogenic protists
Thibaut Poinsignon (Gaëlle lLelandais, DT, Pierre Poulain, co-DT)
Modélisation des réseaux biologiques, analyse de données multi-omiques, visualisation à large échelle
Pr Gaëlle Lelandais, I2BC, Université Paris Saclay
Dr Yi-Kuo Yu, NCBI, NIH, Bethesda, USA
Pr Denis Mestivier, UPEC
Dr Stéphane Lemaire, IBPS, Sorbonne Université
Pr Jean-Louis Guéant, INSERM, Université de Lorraine
Dr Robert Sutac, Biocev, Prague, Rep. Tchèque
Pr Pavel Martasek, 1st Faculty of Medicine, Charles University, Prague, Rep. Tchèque
Data mining, Visualization and Computational Modeling of Redox Signaling Networks – MinOmics
2020-03 to 2024-03 | Grant
National Agency for Research (Paris, FR)
Microbial Communities in Biomedical and Environmental Areas, and Systems Biology
2018-09 to 2022-11 | Grant
European Commission (Brussels, BE)
High performance MS-based proteomics by reducing stable isotopes complexity in vivo – SLIM-labeling
2018-09 to 2022-03 | Grant
National Agency for Research (Paris, FR)
Le protéome urinaire dans l’ataxie de Friedreich : apport de la protéomique quantitative pour la découverte de biomarqueurs 2019-2019-2022 | Grant
Association Française Ataxie de Friedreich (AFAF, Paris FR)
URL : www.afaf.asso.fr