THSWITCH

Decoding genetic switches in T helper cell differentiation

Coordinatore	EUROPEAN MOLECULAR BIOLOGY LABORATORY    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Germany [DE]
Totale costo	1˙330˙634 €
EC contributo	1˙330˙634 €
Programma	FP7-IDEAS-ERC Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	ERC-2010-StG_20091118
Funding Scheme	ERC-SG
Anno di inizio	2011
Periodo (anno-mese-giorno)	2011-01-01   -   2015-12-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	MEDICAL RESEARCH COUNCIL  Organization address address: NORTH STAR AVENUE POLARIS HOUSE city: SWINDON postcode: SN2 1FL contact info Titolo: Ms. Nome: Elizabeth Cognome: Cutler Email: send email Telefono: +44 122 340 2357 Fax: +44 341 2151	UK (SWINDON)	beneficiary	503˙154.00
2	EUROPEAN MOLECULAR BIOLOGY LABORATORY  Organization address address: Meyerhofstrasse 1 city: HEIDELBERG postcode: 69117 contact info Titolo: Dr. Nome: Sarah Amalia Cognome: Polonius-Teichmann Email: send email Telefono: +44 1223 492 520 Fax: +44 1223 494 468	DE (HEIDELBERG)	hostInstitution	827˙480.00
3	EUROPEAN MOLECULAR BIOLOGY LABORATORY  Organization address address: Meyerhofstrasse 1 city: HEIDELBERG postcode: 69117 contact info Titolo: Ms. Nome: Jillian Cognome: Rowe Email: send email Telefono: +49 6221 387 8316	DE (HEIDELBERG)	hostInstitution	827˙480.00

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 Obiettivo del progetto (Objective)

'The central question of this proposal is: how are changes in cell state regulated at the transcriptomic and epigenetic level? I will tackle this question using an integrated computational and experimental approach with the T helper cell system as my model. The Th system consists of a naïve precursor cell type, and four main differentiated cell types that have some capacity to interconvert, known as plasticity. The experiments will be designed to measure both entire transcriptomes and single mRNAs by single molecule RNA-FISH. (i) Quantifying genetic switches. On a genome-wide scale, what is the distribution of gene expression levels in the Th cell types? Do genes have two discrete expression levels (on and off) in terms of mRNAs per cell or a continuous distribution of expression levels? How do epigenetic marks correlate with expression levels? We will use genome-wide RNA-seq and epigenetic ChIP-seq experiments on homogeneous populations of cells coupled with new computational methods. (ii) The molecular nature of the genetic switch. What is the hierarchy and kinetics of molecular events that drive gene expression changes during differentiation and plasticity? Using highly resolved timecourse experiments to profile individual cell generations, we will unravel the temporal order of regulation by transcription factors, microRNAs and epigenetic factors using RNA-seq and ChIP-seq experiments. We will integrate the data computationally to infer new regulatory interactions. (iii) How genetic switches drive cell type switches. Which transcription factors directly regulate cytokines, the phenotypic readout of Th cells? Are the kinetics of these interactions graded or switch-like? What is the extent of stochastic cell-to-cell variation? We will validate predicted transcription factor-cytokine interactions and quantify levels of proteins and mRNA in single cells with fluorescence microscopy experiments, modelling this data probabilistically.'