Eduardo Dias
Name: Eduardo Ferreira Martins Dias
Nationality: Portuguese
Academic Background: BSc in Biology and MSc in Technological and Comparative Molecular Genetics. Both degrees were obtained at the University of Trás-os-Montes and Alto Douro (Vila Real – Portugal).
Project Title: SV-mediated enhancer rearrangements in medulloblastoma
Project Background: Medulloblastoma (MB) is the most common type of pediatric malignant brain tumors. Survival of MB patients has slightly increased in the past years essentially due to the characterization of MB heterogeneity, which is broadly explained by the existence of four molecular tumor subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4. Among these MB subtypes, Group 3 and Group 4 tumors are the most poorly characterized, show the worst prognosis and exhibit a high prevalence of metastasis at diagnosis, thus demanding a higher incidence of studies and more effective therapies.
According to the recently published datasets from Group 3 and Group 4 tumors, these two MB subtypes share some genetic mutations and copy-number alterations but there are many tumors that do not display any genomic aberration described so far. In this context, our studies have implicated an unexpected role for structural variations (SVs) in gene (dys)regulation through a mechanism that we have designated as ‘enhancer hijacking’. Briefly, different classes of genomic SVs (e.g. deletions, duplications, inversions) can place highly active enhancers close to normally silent oncogenes, causing their expression upregulation. Although this may represent a very important process underlying Group 3 and Group 4 MB development and progression, the enhancer hijacking mechanism remains ill understood and experimental evidence is lacking to support it.
Project Aim: The main aim of my research project is to identify, characterize and functionally validate enhancer hijacking mechanisms mediated by SVs in Group 3 and Group 4 MB samples. On top of this main aim, this project involves two distinct objectives: (1) a genome-wide analysis of altered enhancer-promoter interactions in order to study global consequences of SVs in MB; and (2) a high-depth analysis of altered enhancer-promoter interactions focusing on specific loci that we have identified as recurrent targets of enhancer hijacking mechanisms.
Expected Outcome: Results from this research project may have both biological and clinical relevance as they will hopefully show how SV-mediated enhancer rearrangements can activate oncogenes in Group 3 and Group 4 MB tumors. The characterization and functional validation of enhancer hijacking mechanisms in these poorly understood MB subtypes may both lead to earlier patient diagnosis and provide novel therapeutic targets in order to develop efficient therapies for patients with this devastating disease.
Project Description: If stretched out, the DNA in a single human cell has a length of around 2 meters. However, it is composed of just 4 different constituent bases or also called nucleotides (adenine, cytosine, guanine, and thymine) that are arranged in a specific order/sequence. The DNA sequence varies from person to person and this explains why I have distinct physical and psychological features compared to you. The body of an average adult contains between 30 and 40 trillion cells. Our cell number is maintained within this interval through a balance between cell proliferation and death. Cell proliferation occurs when cells divide themselves to generate daughter cells, a process that implies an error-free copy of the genetic information to the daughter cells. This is critical to prevent the accumulation of genetic defects (mutations) throughout cell proliferation. Otherwise, the accumulation of DNA mutations may result in the onset of diseases such as cancer.
Genetic mutations can be of several types; they can go from substitutions of a single nucleotide (the so-called single nucleotide variants – SNVs) within gene regions to gains/losses of whole chromosomes. My research project will investigate the role of another class of DNA mutations – structural variations (SVs) – in medulloblastoma, which is a highly malignant brain cancer that occurs predominantly in childhood. SVs consist of rearrangements of the genome structure that usually affect large sets of genes. In cancer, genomic SVs deserve a special attention as they can affect genes responsible for the prevention of tumor development and progression (tumor suppressor genes) and/or genes with tumor-promoting functions (oncogenes). There are cases of tumors in which normally silent oncogenes are activated without showing any mutation within their DNA sequences. In order to explain these phenomena, our studies have demonstrated that SVs are able to activate oncogenes by placing them close to genomic regions containing highly active enhancers (regulatory DNA elements responsible for gene activation). We have designated these SV-mediated genomic rearrangements as ‘enhancer hijacking’ mechanisms. In summary, the aim of my research project is to identify, characterize and functionally validate enhancer hijacking mechanisms mediated by SVs in the most aggressive medulloblastoma subtypes – Group 3 and Group 4. Future results will hopefully demonstrate that each of these medulloblastoma subgroups has specific and recurrent SV-mediated enhancer rearrangements that cause the activation of target oncogenes. Consequently, this project may have an important contribution to a faster and more accurate patient diagnosis, as well as to uncover novel therapeutic targets which will serve as a basis for developing efficient therapies for patients with this devastating disease.
Contact: eduardo.dias@bric.ku.dk