WHYMIR

Interplays between miRNAs and transcription factors in the determination and maintenance of cell identity

Coordinatore	UNIVERSITAET BASEL    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Switzerland [CH]
Totale costo	891˙759 €
EC contributo	891˙759 €
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-2012-StG_20111109
Funding Scheme	ERC-SG
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-11-01   -   2015-10-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITAET BASEL  Organization address address: Petersplatz 1 city: BASEL postcode: 4003 contact info Titolo: Dr. Nome: Kurt Cognome: Kamber Email: send email Telefono: +41 61 2672833	CH (BASEL)	hostInstitution	891˙759.00
2	UNIVERSITAET BASEL  Organization address address: Petersplatz 1 city: BASEL postcode: 4003 contact info Titolo: Prof. Nome: Mihaiela Luxita Cognome: Zavolan Email: send email Telefono: +41 61 267 15 77 Fax: +41 61 267 15 85	CH (BASEL)	hostInstitution	891˙759.00

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 Obiettivo del progetto (Objective)

'miRNAs are small RNAs that guide the RNA-induced silencing complex to mRNA targets, destabilizing them and inhibiting their translation. Much has been learned about their involvement in organism development and function, yet some striking puzzles remain. On the one hand it has been shown that miRNAs are essential for development, and the preferential targeting of transcription factors (TFs) by miRNAs suggests that miRNAs and TFs 'coordinate' to regulate gene expression. Furthermore, studies in the past year concluded that, on their own or in combination with TFs, miRNAs can induce reprogramming of somatic cells into induced pluripotent stem cells (iPSC). On the other hand, high-throughput measurements of mRNA and protein level changes upon miRNA transfections suggest that miRNAs have largely a 'fine-tuning' function. These small effects on individual genes must, however, confer a substantial selective advantage, because many target sites remain conserved over long evolutionary distances. Here I first propose to investigate the hypothesis that instead of primarily affecting the average levels of target genes, miRNAs reduce the cell-to-cell variation in gene expression, affecting precisely the steps that determine the intrinsic noise. I will then use miRNA-mediated reprogramming of somatic cells into iPSCs as a model system to directly investigate the 'coordination' between miRNAs and TFs in determining cell identity and differentiation. Through determination of miRNA targets with Argonaute crosslinking and immunoprecipitation, mRNA sequencing and methylated DNA immunoprecipitation I attempt to retrace the regulatory interactions that lead from induction of a few miRNAs, through perturbation of TF activities, to the activation of 'stemness' genes. Finally, following up on preliminary results obtained in my lab, I will investigate the function of miRNA targeting in the nucleus, that potentially couples transcriptional and post-transcriptional regulation more directly.'