Project description
Chromatin regulation in haematopoiesis
Chromatin factors (CFs) drive cellular fate and developmental lineage decision by participating in dynamic chromatin complexes and regulating gene expression. Given that CFs are among the most frequently mutated proteins in various blood malignancies, as for example in mixed lineage leukemia (MLL), the EU-funded ChRONAM-H project set out to determine the role of these proteins in haematopoietic lineage commitment. Through state-of-the-art chromatin profiling technologies, scientists will link CFs with transcription factors in both normal and malignant haematopoiesis. Results will provide fundamental information on genome regulatory mechanisms and also identify molecular targets to fight leukemia.
Objective
Chromatin Factors (CFs) comprise a diverse family of proteins that elicit key regulatory epigenetic activities during the regulation of cellular fates. Although this heterogeneous group has been traditionally considered a static toolkit of epigenetic enzymes deployed to lineage-specific loci under the control of Transcription Factors (TFs), recent works have shown that CFs are crucial determinants of developmental lineage decisions that assemble into dynamic chromatin regulatory complexes with exquisite cell-type-specific composition. Hematopoiesis is a key developmental process largely dependent on Chromatin Factors. Importantly, CFs are the most recurrently mutated protein category across diverse blood malignancies. In fact, alterations in some of these proteins, like MLL fusions, have been proven to be central drivers of malignant transformation. However, in spite of this proven relevance, the contribution of most Chromatin Factors to blood lineage commitment remains largely unexplored; moreover, even for well-studied complexes such as SWI/SNF Polycomb or COMPASS, very little is known about the mechanisms that govern their locus-specific assembly and activity during cell fate specification.
My project Chromatin Regulation Of Normal And Malignant Haematopoiesis (ChRONAM-H) proposes a multidisciplinary framework to explore the functions of CFs during hematopoietic lineage commitment and malignant transformation. I will combine high-throughput functional measurements with state-of-the-art chromatin profiling technologies to unveil the lineage specifying roles of a large number of CFs and orthogonally link them within existing TF-centric networks in both normal and malignant hematopoiesis. This will shed light on the molecular behavior of chromatin regulatory complexes, providing new insights about the genome regulatory mechanisms that orchestrate hematopoiesis and how they might be therapeutically targeted to fight leukemia.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
CB2 1TN Cambridge
United Kingdom