Descrizione del progetto
Regolazione della cromatina nell’ematopoiesi
I fattori cromatinici (CF, Chromatin Factors) guidano il destino cellulare e la decisione del lignaggio evolutivo partecipando a complessi di cromatina dinamica e regolando l’espressione genica. Considerando che i CF sono tra le proteine più frequentemente mutate in varie neoplasie del sangue, come ad esempio nella leucemia da lignaggio misto, il progetto ChRONAM-H, finanziato dall’UE, si è prefisso di determinare il ruolo di tali proteine nell’impegno di lignaggio ematopoietico. Attraverso tecnologie di profilatura della cromatina all’avanguardia, gli scienziati collegheranno i CF con i fattori di trascrizione nell’ematopoiesi sia normale che maligna. I risultati forniranno informazioni fondamentali sui meccanismi regolatori del genoma e identificheranno anche obiettivi molecolari per combattere la leucemia.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
CB2 1TN Cambridge
Regno Unito