“Causes and consequences of pluripotency gene regulatory network member heterogeneity”

Información del proyecto

CACOHET

Identificador del acuerdo de subvención: 660295

DOI

10.3030/660295

Proyecto finalizado el 2 Septiembre 2017

Fecha de la firma de la CE 22 Abril 2015

Fecha de inicio 1 Agosto 2016

Fecha de finalización 31 Julio 2018

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 183 454,80

Aportación de la UE

€ 183 454,80

Coordinado por

THE UNIVERSITY OF EDINBURGH
United Kingdom

Objetivo

How stem cell populations balance the opposing forces of self-renewal and differentiation to maintain a functional population is a question that strikes at the heart of what it means to be a stem cell. Undifferentiated embryonic stem cell (ESC) identity is maintained by transcription factors (TFs) of the pluripotency gene regulatory network (PGRN) centred on the TFs Oct4, Sox2 and Nanog. ESCs with high levels of Nanog self-renew efficiently while ESCs with low Nanog levels are prone to differentiate. Therefore, the observed heterogeneous expression of some PGRN components, in particular Nanog, is likely to be important for simultaneous maintenance of self-renewal and facilitation of differentiation, thereby sustaining functional pluripotency. In this proposal I will unravel mechanisms establishing heterogeneity and characterise the role of Nanog in generating ESC heterogeneity. By determining chromatin binding dependencies between TFs and by using a novel approach to identify functional cis-elements that mediate Nanog action, these studies will illuminate mechanisms regulating ESC phenotype. The hypothesis that pluripotency is generated by heterogeneity in PGRN component expression, that then generates an ESC population in which single cells have distinct intrinsic probabilities for differentiation into specific cell types will be tested. Interfering with PGRN component function locus-specifically using a high efficiency genome engineering strategy, will explore a new method to influence cell-fate. Together, the proposed innovative experiments aim to increase the understanding of the causes and consequences of PGRN component heterogeneity and the regulation of pluripotency that may be of relevance to other stem cell systems. The results will have important implications for ESC biology, in terms of increasing the efficiencies of ESC derivation, differentiation, and the use of ESCs in future cell based regenerative medicine approaches.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › genética › ADN
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias médicas y de la salud › biotecnología médica › tecnologías celulares › células madre
• ciencias naturales › ciencias biológicas › genética › genoma

Palabras clave

• Pluripotency
• Embryonic stem cells
• Nanog
• transcription factor networks
• heterogeneity
• retrospective analysis of pluripotency factor binding
• DCM methylation

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF)
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2014

Coordinador

THE UNIVERSITY OF EDINBURGH

• Aportación neta de la UEn: € 183 454,80
• Dirección: OLD COLLEGE, SOUTH BRIDGE ; EH8 9YL Edinburgh ; Reino Unido
• Región: Scotland › Eastern Scotland › Edinburgh
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 183 454,80