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4DCELLFATE — Result In Brief

Project ID: 277899
Funded under: FP7-HEALTH
Country: Spain

Epigenetic regulator complexes in health and disease

Epigenetic regulator complexes — nucleosome remodelling and deacetylation (NuRD) complex and Polycomb repressive complexes (PRCs) — are involved in cell fate decisions of embryonic stem cells (ESCs). These complexes are also implicated in the development of cancer stem cells, such as in leukaemia.
Epigenetic regulator complexes in health and disease
A major roadblock to fully exploiting the potential of full-genome sequencing is to truly understand how the information in each genome is actually used. Intriguingly, this is often controlled by so-called epigenetic regulation, which changes the output but not the sequence of the genome. Epigenetic changes can be pre-programmed but can also come from the environment.

The EU-funded 4DCellFate project would like to set the basis for understanding the 'epigenetic code'. Such a code guides the epigenetic regulation of cells during differentiation, for instance by telling an embryonic stem cell (ESC) what type of cell it should differentiate into (a muscle cell, a nerve, etc.). Often, such epigenetic guides are misregulated during diseases, such as cancers, and may even have causative effects.

A multidisciplinary consortium comprised of academic and industrial partners has been brought together in 4DCellFate to analyse two major epigenetic regulatory complexes: PCR and NuRD. 4DCellFate scientists will characterise changes in structure and function of the PRC and NuRD complexes in ESC differentiation and cancer. For this, they will use state-of-the-art techniques, including ChIP-seq analysis, X-ray crystallography, mass spectrometry (MS) and electron microscopy, to study the interactions between proteins, nucleosomes and nucleic acids over time and space dimensions.

Several significant discoveries have been made so far. Accurate structure and compositions of NuRD and PRC1/2 complexes were obtained along with potentially useful novel interacting molecules using ChIP-seq in mouse ESCs (mESCs). A flexible, sensitive and high-throughput genetic screening technique was developed for testing cell lines using a small interfering RNA (siRNA) library. This will be used to identify Polycomb regulators in mESCs.

Technical breakthroughs will also help move the project forward. For instance, a novel high-throughput protein crystallisation and X-ray structure determination tool called MultiTRAQ was developed for rapidly characterising protein complexes using MS that considerably shortened processing times from over a year to only a few days. Protocols were also developed to automate the identification of structures in NuRD and PRC1/2 complexes. Finally, multi-protein expression was achieved with a MultiBac-based expression technique along with purification protocols for NuRD and PRC complexes.

Data integration is ongoing for a comprehensive analysis of temporal variations of NuRD and PRC complexes during ESC differentiation. Small molecule screening will be set up to identify potential inhibitors or compounds that can modulate activity in these complexes to alter cell fate decisions.

Research results are disseminated through publications in several peer-reviewed journals as well as on the project website. Elucidating epigenetic complexes could also optimise the selective differentiation of induced pluripotent stem (iPS) cells, providing more options for stem cell cancer therapy and regenerative medicine.

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