Developing a global understanding of the PRC and NuRD complexes in stem cell differentiation, in health and disease

Title Developing a global understanding of the PRC and NuRD complexes in stem cell differentiation, in health and disease
Acronym 4D-CellFate
Start date 2011-12-01
End date 2016-11-30
Sponsor European Commission
Institution Centre for Genomic Regulation (CRG)

Associated cell lines

Project Description

Embryonic stem (ES) cells have the potential to differentiate into all different cell as well as renew indefinitely in culture, holding great therapeutic potential for personalizedmedicine. However, the molecular mechanisms underpinning cell fate decisions by individual cells are poorly understood. There is compelling evidence that two large multi-proteinmachines, the Nucleosome Remodelling and Deacetylation (NuRD) complex and the Polycomb Repressive Complexes (PRCs), modulate chromatin structure to control stem cellrenewal, lineage commitment and differentiation. Importantly, they are clearly implicated in cancer. The main goal of 4D-CellFate is to understand how the PRC/NuRD complexes and their plethora of interactions (protein/protein, protein/nucleosome, protein/nucleic acids)regulate cell fate. To obtain this global, quantitative and dynamic – 4D – understanding of the structure/functions of these two multi-protein machines during ES cell differentiationand in different disease states, we propose a large scale multi-disciplinary “data-gathering” approach combining European excellence in interactomics (affinity purification,quantitative mass spectrometry-based proteomics, ChIP-Seq analysis, light microscopy), structural biology (X-ray crystallography, NMR, native-state mass spectrometry, ElectronMicroscopy, biochemistry/biophysics), cellular, tumor, and computational biology. We expect to significantly advance the technology, mainly in the fields of proteomics, structuralbiology, and small molecule screening, and to make our knowledge, reagents and data publicly available to the scientific community. The ultimate outcome of 4D-CellFate will be to lay the foundations for understanding the role of the PRC/NuRD complexes in human development and cancer, specifically inleukaemogenesis. Three SMEs and one large multi-national pharma will be actively involved ensuring that the knowledge generated can be translated into new ways to control complex diseases.