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Cell cycle regulation of ES cell identity and reprogramming potential

Coordinatore	IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	2˙038˙170 €
EC contributo	2˙038˙170 €
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-2011-ADG_20110310
Funding Scheme	ERC-AG
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-05-01   -   2017-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE  Organization address address: SOUTH KENSINGTON CAMPUS EXHIBITION ROAD city: LONDON postcode: SW7 2AZ contact info Titolo: Mr. Nome: Scott C. Cognome: Wheatley Email: send email Telefono: +44 207 594 3866	UK (LONDON)	hostInstitution	2˙038˙170.00
2	IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE  Organization address address: SOUTH KENSINGTON CAMPUS EXHIBITION ROAD city: LONDON postcode: SW7 2AZ contact info Titolo: Prof. Nome: Amanda Cognome: Fisher Email: send email Telefono: -9135 Fax: -8884	UK (LONDON)	hostInstitution	2˙038˙170.00

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 Obiettivo del progetto (Objective)

'Pluripotent embryonic stem (ES) and germ (EG) cells differ from other stem cells in several respects. They display a characteristically ‘compressed’ cell cycle in which G1 is shortened, contain a high proportion of cells in DNA synthesis (S)-phase and lack several cell cycle checkpoints. This unusual cell cycle signature is important for maintaining their identity since cell cycle arrest, or lengthening, results in irreversible differentiation, and somatic cells assume this unusual signature when successfully reprogrammed.

We have shown that ES and EG cells rapidly convert somatic cells towards pluripotency in transient heterokaryons, and this can be enhanced by genetic modification or using ES cells enriched at G2-phase. On the other hand, mouse epiblast stem (EpiS) and ES cells that lack specific repressor activities (such as Polycomb) although pluripotent, do notdominantly convert somatic cells and show increased doubling times. To determine the importance of cell cycle control for pluripotent self-renewal, we have optimised elutriation to allow the isolation of ES, EG and EpiS cells at progressive stages of the cell cycle. Pilot studies show changes in the levels of modified histones as ES cells transit the cell cycle, and increased levels of specific reprogramming factors during G2-phase. We will extend these analyses genome wide (using ChIP and RNA Seq, and high throughput proteomics) and use fluorescent microscopy to document changes in chromatin dynamics during ES cell cycle, and during somatic cell reprogramming. This will be achieved using novel micro-fluidic approaches to generate heterokaryons between ES, EG, EpiS and lymphocytes. The importance of cell cycle stage and its relevance during early events in successful reprogramming will be tested in heterokaryon and hybrid assays using conditional mutant cells, RNAi-based approaches and cell cycle inhibitors to block critical components.'