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

4DCellFate news article in EMBO encounters

EMBO Encounters recently published the following news article we submitted about the 4DCellFate project:

The fate of stem cells in four dimensions

An ambitious new project, 4DCellFate (www.4dcellfate.eu), will study the roles of the Nucleosome Remodeling and Deacetylase (NuRD) and Polycomb Repressive (PRC) complexes in regulating differentiation in embryonic stem cells.

The goal is to create a “four-dimensional map” across space (the genome and cell) and time (during differentiation) of the regulatory functions of these complexes. The project is funded by a European Commission Seventh Framework Programme (FP7) grant of almost Euros 12 million and brings together scientists from eight academic institutes, three biotech companies, and a large pharmaceutical company. The project will play a key role in training future scientists in multidisciplinary science, both within and outside the consortium, and will recruit and involve additional young investigators.

Although it has been known for over a decade that these complexes play a fundamental role in determining stem cell fate, how these complexes work remains very unclear. Recent studies have shown that the NuRD and PRC complexes are not static entities, but rather that their compositions and structures are dynamic. A key goal will be to understand this complexity and determine how their activity is modulated at a system-wide level. Initially, the project will elucidate the composition, genome-wide localization, and structures of these complexes. The next step is to understand how the activities of the complexes are regulated. The project will use high-throughput genomics, epigenomics, and quantitative mass spectrometry, and will develop novel methods for studying the localization of proteins at a single-molecule level. The aim is to integrate the data into a multi-scale model of gene regulation by the NuRD and PRC complexes during self-renewal and stem cell differentiation.

“A major goal of the project is to translate the understanding of the roles of these complexes in stem cells into future molecular therapies. In particular, the project will look at the epigenetic processes that deregulate gene expression in cancer, specifically during the onset, development or progression of leukaemia,” said Luciano Di Croce, Research Professor at the Centre for Genomic Regulation, Barcelona, and Scientific Coordinator of the 4DCellFate project. Ernest Laue, Professor at the University of Cambridge, remarked: “We believe that elucidating the details of how the PRC and NuRD complexes regulate stem cell differentiation will have significant potential for studying disease progression, and for the development of drugs for personalised molecular therapies.”