Single cell transcriptome analyses of microglia inflammatory response during development

Type de poste
Niveau d'étude minimal
Dates
Durée du poste
Contrat renouvelable
Contrat non renouvelable
Date de prise de fonction
Date de fin de validité de l'annonce
Localisation
Nom de la structure d'accueil
Adresse

NeuroDiderot- Inserm UMR 1141
Bâtiment Bingen - 3ème étage
75019 Paris
France

Contacts
Andrée Delahaye-Druiez
Philippe Nghe
Juliette Van Steenwinckel
Email du/des contacts
andree.delahaye@inserm.fr
philippe.nghe@espci.fr
juliette.van-steenwinckel@inserm.fr
Description

Summary:
Microglia, the resident immune cells of the brain, rapidly change states in response to their environment. Recently, single cell whole transcriptome mRNA sequencing of microglial cells revealed microglia heterogeneity particularly at young age. Several new subtypes of microglia were described based on their gene expression signatures and markers. In collaboration with ESPCI researchers, we developed a single cell targeted mRNA sequencing test to better delineate and specifically track microglia subpopulations during brain development in a mouse model of perinatal neuroinflammation. The objective of the project is to develop a reproductible analysis workflow specific to the new single cell targeted RNAseq data, from quality control and preprocessing, to the final comparative analysis. A particular attention will be provided to the finetuning of the relevant parameters.

Description:
Microglia, the CNS macrophage is one of the major players in neuroinflammatory processes. We will take advantage of the U1141 laboratory expertise in neuroinflammation during development [1]. Within the laboratory, a mouse model based on systemic injections of interleukin-1 beta (IL-1β) between P1 and P5 (Postnatal day 1 and 5) has been developed [2]. In this model, microglia were purified ex vivo to apply genome-wide transcriptomics analysis.
For the project, we will design an integrated analysis framework using existing and newly generated transcriptomics data on this same mouse model of perinatal neuroinflammation (with two conditions: inflammation with IL-1 β, and control with PBS). Whole and targeted single cell RNAseq data will be generated for each condition. Standard workflow for whole single cell RNAseq will be used to identify specific cell clusters in our model. The identified cell clusters will be compared and crossed-checked with other published single cell genome-wide expression studies of microglia in mice (GSE121654, GSE123025). The newly developed targeted single cell workflow will allow to follow the dynamics of some microglial cells subtypes in response to inflammation during development. Understanding the microglial cell population changes could help to develop effective therapies aimed at preventing the onset of brain damage and neurodevelopmental disorders.
The selected candidate will be embedded in the NeuroDiderot research unit that gathers researchers working on neurodevelopmental disorders using transcriptome-based approaches [3], [4], [5] in collaboration with the Biochemistry Laboratory at ESPCI, which developed the technology for single cell analysis of gene panels. S/he will have the opportunity to gain a high level of competence in the highly demanded area of single-cell transcriptome analysis.

Expected skills:
The ideal candidate would combine:
- Proficiency with at least one programming language (R and/or Python) and with bash/shell scripting
- Experience in working on a high-computing cluster and with a UNIX environment would be appreciated
- Interest/skills in bioinformatics data analysis, or in data science and processing in general, in multivariate statistics
- Ability to work independently and collaboratively

How to apply?
Interested candidates should submit an application either in English or French to andree.delahaye@inserm.fr with a detailed CV and a motivation letter.
The desired starting date is anytime between January and June 2020.

References:
[1] H. Hagberg et al. “The role of inflammation in perinatal brain injury,” Nat. Rev. Neurol., 2015.
[2] G. Favrais et al. “Systemic inflammation disrupts the developmental program of white matter,” Ann. Neurol., 2011.
[3] M. L. Krishnan et al. “Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants,” Nat. Commun., 2017.
[4] A. Delahaye-Duriez et al. “Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery”, Genome Biol., 2016.
[5] J. Van Steenwinckel et al. “Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain”, Brain, 2019.

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