LINKER · Elucidating transcriptional rewiring on hematological malignancies via computational methods
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-03-01 → 2022-02-28
- EU contribution
- €172,932
- Participants
- 1
- Scheme
- MSCA-IF-EF-RI
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Results in brief
Elucidating transcriptional rewiring on hematological malignancies via computational methods
Genes and their corresponding pathways form networks that regulate various cellular functions critical in tumor development and response to therapy. These networks, termed gene regulatory networks, define the regulatory relationships among genes and provide a concise representation of the transcriptional regulatory landscape of the cell. Therefore, the construction and exploration of the topology of such networks and their constituents can help us understand the biological mechanisms of cancer. The rapid growth of biomedical cancer datasets has created an urgent need for highly scalable computational tools that can make sense of these biomedical “big data” and extract biological and medical insights from them. Hence, it is of uttermost importance to i) develop robust and efficient methods to uncover gene regulatory networks from high throughput sequencing data; and ii) given those networks, develop efficient differential network analysis methods that will shed light into the transcriptional rewiring associated with a particular phenotype. To achieve these goals, in this action we extended and optimized a computational method, termed LINKER that builds Gene Regulatory Networks from high-throughput sequencing data, and scores them for evidence of significant transcriptional rewiring between phenotype groups. We then validated the developed method using publicly available resources, and finally, we applied it to elucidate biomarkers associated with disease progression on hematological malignancies. Therefore, the overarching goal achienved on this proposal was to build computational models to elucidate the transcriptional rewiring associated with disease progression on hematological malignancies. This goal was achieved through the development of computational methods to uncover dynamically-regulated GRNs, and applied to elucidate transcriptional rewiring on hematological malignancies.
Data: CORDIS, © European Union
Project objective
Genes and their corresponding pathways form networks that regulate various cellular functions that are critical in tumor development. These networks, coined Gene Regulatory Networks (GRNs), define the regulatory relationships among genes and provide a concise representation of the transcriptional regulatory landscape of the cell. Further, different phenotypes can lead to activation of different functional pathways by different global rewiring of the underlying GRNs. To uncover such transcriptional rewiring, in this project I will further advance and optimize a recent efficient computational method developed by myself, coined LINKER, aiming at uncovering GRNs from RNAseq data; and given those networks, develop efficient differential network analysis methods that will shed light into the regulatory rewiring associated with phenotype. As one of the key goals of this proposal is the translation of computational methods to advance clinical cancer knowledge, I will work with the hosting group to apply LINKER to uncover the transcriptional rewiring associated to hematological malignancies. Specifically, I will apply LINKER in a stepwise model first on available RNA-seq data from multiple myeloma and acute myeloblastic leukemia, and second to primary data from patients with these diseases provided by the hosting supervisor. Rewired GRNs between MM and normal BM plasma cells and between leukemic blast and normal hematopoietic progenitor cells, potentially implicated in the pathogenesis of the disease, will be functionally validated by state of the art gain and loss of function technologies (CRISPR/cas9). As data provided by the host institution includes clinical follow up from patients we will also examine the prognostic value of our identified GRN. I envision that LINKER will provide additional novel insights to our understanding of the key rewiring associated with these malignancies, increased by our ability to translate the discovered biomarkers to patient treatment.
Original text from CORDIS.
Participants
- FUNDACION PARA LA INVESTIGACION MEDICA APLICADA FIMA · PamplonaCoordinatorSpain
Links
Data: CORDIS, © European Union