IP: Dra. Biola M. Javierre

Resumen del proyecto: Most of mutations and epimutations associated with complex diseases lie in non-coding regions, frequently at regulatory regions such as enhancers, and potentially exert their functions by altering the regulation of the target genes. The vast majority of regulatory elements that regulate transcriptional activity of each gene in each cell type are unknown, constituting a major missing link in understanding genome control. Therefore, a large amount of useful information on the potential non-coding genetic and epigenetic determinants of disease is currently un-exploitable. Motivated by this limitation, we previously developed a new method called Promoter Capture Hi-C, which allows the pioneer genome-wide systematic identification of the long-range regulatory elements that control more than 20,000 genes. Using this method to analyse seventeen differentiated human blood cell types, I connected for the first-time non-coding autoimmune disease variants to putative target promoters, prioritizing hundreds of disease-candidate genes, three quarters of which had not been previously implicated. Now, I want to step forward and to approach acute lymphoblastic leukaemia (ALL), the most common childhood tumour, which also has a high incidence in adults. ALL is a complex disease with a clear genetic and epigenetic component that needs novel molecular targets for improving therapeutic strategies and increasing survival rate. Based on preliminary data recently generated by my newly established group, I hypothese that the novel description of the regulatory elements that control each gene along early human B lymphopoiesis could allow: i) to better understand cell differentiation, haematopoiesis and B cell biology, ii) to understand the contributions of non-coding mutations and epimutations in B-precursor ALL, and iii) to discover new genes potentially implicated in malignant transformation that could be novel therapeutic targets. First, we will develop a novel experimental and computational methodology to genome-wide detect distal interacting regions of the genome for all genes in rare cell types. Second, using this new methodology, we will unravel the dynamic rewiring of promoter interactions with regulatory elements along early B cell differentiation. Third, we will link non-coding mutations and epimutations to their putative target genes, describing potential novel genes and gene pathways associated with B-ALL In summary, this interdisciplinary project will provide unprecedented insights into our understanding of how cells decide their identity with impact, not only on B cell malignancies, but also on regenerative medicine, autoimmunity and immunodeficiency.

Entidad financiadora: European Hematology Association