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FUNDACIO CENTRE DE REGULACIO GENOMICA

Country: Spain

FUNDACIO CENTRE DE REGULACIO GENOMICA

211 Projects, page 1 of 43
  • Funder: European Commission Project Code: 101065294
    Funder Contribution: 181,153 EUR

    Scleractinian corals are the main builders of the marine reefs that provide a home to roughly a quarter of all marine species. In addition, their photosynthetic symbionts contribute to Earth’s oxygen, absorb CO2 from the atmosphere, and provide the coral host with most of its metabolic needs. Global changes drastically affecting ocean acidification and temperatures cause the breakdown of this symbiosis. This process is also known as coral bleaching, and it results in a mass decline in coral reefs. Despite the continuous efforts to study this phenomenon, our understanding of the bleaching process is so far limited. It is important to emphasize that different coral species, display distinct responses to stressors, with varying mortality rates following bleaching. Hence, in this action, I will utilize these differences in coral resilience (i) to characterize the cellular and molecular responses to stressors of three corals with different levels of bleaching resilience (Stylophora pistillata, Acropora millepora, and Oculina patagonica); (ii) to identify specific genes that might be key players in coral resilience, and (iii) to design and test pharmacological interventions to modulate coral resilience to thermal and acidification stress. To do so, I will expose corals to thermal and acidification stressors and use single-cell genomics approaches to measure and compare cell type-specific gene expression responses to stressors within and between species. These analyses will highlight candidate molecular pathways and cellular processes responsible for the high resilience of some of these species. Together, this project will provide a high-resolution molecular map of stony coral responses to climate change-related stressors, and it will help me, and others advance towards targeted interventions to ameliorate these effects.

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  • Funder: European Commission Project Code: 101062382
    Funder Contribution: 165,313 EUR

    Inflammatory Bowel Diseases (IBD) affected more than 6.8 million people worldwide in 2017, and Chronic Obstructive Pulmonary Disease(COPD) caused 3.23 million deaths in 2019. Both illnesses present a disturbance in the quantity and quality of mucus due to an abnormal expression and secretion of mucins. The mucins are the main component of mucus and are specifically expressed in cells and tissues. Mucin secretion is crucial for the normal physiology of wet mucosal epithelium. Growing data shows that alterations in mucins expression and their localization are related to pathological processes, such as inflammation, infection, autoimmunity, and cancer. All mucins are synthesized in the endoplasmic reticulum and exported to the Golgi complex, and after extensive glycosylation, are transported to the plasma membrane. However, how these mucins are sorted and packed into granules that can reach micrometers in size remains largely unknown. I hypothesize that transmembrane and secreted mucins are sorted and packed in separate containers by regulatory partners, different from those involved in other bulky-cargo pathways – as collagen –. The Malhotra lab is a world-leader in the study of protein secretion. Recently, I have tagged mucins with fluorescent proteins by CRISPR/Cas9 gene-editing technology, which will allow me to understand these glycoproteins from synthesis to functional target. Unveiling this fundamental knowledge could stimulate the development of therapies aimed to modulate the expression and precise release of mucins, both in pathologies due to mucin hyposecretion – such as IBD – and hypersecretion – observed in COPD –.

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  • Funder: European Commission Project Code: 101152740
    Funder Contribution: 165,313 EUR

    Thousands of Conserved Non-coding Elements (CNEs) are shared by jawed vertebrates, some of which were shown to be important developmental enhancers. However, how these intriguing elements evolve at the functional level and why they are so conserved in sequence remain some of the biggest mysteries in the field of regulatory genomics. In this project, I build a novel view of CNE function and evolution based on my preliminary data and recent breakthroughs on enhancer pleiotropy. This working hypothesis posits that CNEs are ancient transcription factor binding hubs that act as dynamic multi-genic regulators to which new gene targets can be added/removed during evolution. Taking advantage of the exceptional conservation of CNEs, I propose the experimental framework to test this hypothesis on orthologous elements across major vertebrate clades using cutting-edge methodology combining Capture-HiC, RNA-seq and ATAC-seq in shark, chicken and mouse. This approach will provide comparative CNE-target contact maps that will reveal conserved as well as gained and lost interactions in each species, whose functional impact will be tested using CRISPR knockout and interference in mouse neuronal differentiation. In summary, this project will address long-standing questions on the evolution of the regulatory genome and offer insights into the flexibility of enhancers to acquire and lose targets in evolution, expanding our understanding on the pervasiveness and evolution of regulatory pleiotropy.

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  • Funder: European Commission Project Code: 825176
    Overall Budget: 145,000 EURFunder Contribution: 145,000 EUR

    Targeted precision medicine combined with companion diagnostics will provide the basis for future more effective more economic patient care. Recent advances in breast cancer treatment combining inhibitors of poly-ADP-ribose polymerase (PARP1) in conjunction with other targets are at the forefront of this new advance both at the level of basic research and pharmaceutical interest, due to its pivotal role in gene expression, chromatin and repair. We have discovered a key enzyme downstream of PARP1 which generates ATP locally in the nucleus; NUDIX5. This enzyme is overexpressed in cancer and correlates with poor prognosis, as the activity of this enzyme is essential for changes within the 3D chromatin structure, gene regulation and the proliferation of cancer cells. We have developed inhibitors of NUDIX5 in addition to a companion diagnostic, and propose to prove using a multi-disciplinary, international collaborative effort that they can be used to determine not only patient risk and treatment options but also provide an exciting new avenue for the combinatorial treatment of breast and (we hope) other cancer patients.

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  • Funder: European Commission Project Code: 852343
    Overall Budget: 1,996,900 EURFunder Contribution: 1,996,900 EUR

    Epigenetic regulation and metabolism are of great interest in cancer research. However, physical and functional connections between these two areas remain largely unexplored. While it is commonly believed that metabolites can randomly distribute inside the cell, recent evidence rather favors the hypothesis that production of certain metabolites in specific subcellular compartments orchestrates different cellular processes. EPICAMENTE aims at exploring whether the localization of enzymatic activities on chromatin can integrate cancer metabolism with chromatin remodeling to control epigenetic regulation and tumor progression. First, I aim at providing a dataset of chromatin-bound metabolic enzymes in a comprehensive panel of cancer cell lines. By combining a chromatin fluorescent reporter cell line strategy with epigenomic approaches, I will define the epigenetic and transcriptional scenarios orchestrated by chromatin-bound metabolic enzymes, and investigate their relevance in cancer cell proliferation. Performing genetic screenings with the chromatin fluorescent reporter cell lines will allow the identification of genetic interactors mediating the epigenetic role of chromatin-bound metabolic enzymes. In parallel, I aim to screen for small molecules able to counteract the epigenetic states mediated by those metabolic enzymes. Finally, I will validate my results in in vivo cancer models, thus adding an important translational aspect to the project, and opening up new opportunities for cancer therapy. The success of this project can impact our fundamental understanding of cellular and cancer biology. In most cases, the belief is that intracellular materials reside inside steady-state membrane-based compartments, which limit the interactions between different molecular pathways. By describing the role of chromatin-bound metabolic enzymes and discovering direct connections between cancer metabolism and epigenetic regulation, I will scrutinize this belief.

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