Project description DEENESFRITPL Contribution of DNA breaks to neuronal cell genetic heterogeneity Neural progenitor cells undergo tens of thousands of divisions to generate the billions of human brain neurons. This replication stress can lead to recurrent DNA break clusters, creating somatic genomic diversity. The unbalanced genomic mosaicism in neural progenitor cells may result in brain cancer and neuropsychiatric disorders. The EU-funded BrainBreaks project aims to investigate whether cell-autonomous DNA lesions, acquired during progenitor cell division, contribute to the genetic heterogeneity in neuronal cells. The researchers will employ in vitro cell line-based tools, in vivo mouse models and cutting-edge multi-omics approaches to uncover the genomics mechanisms that will provide valuable new insights into neuropsychiatric disorders and tumour biology. Show the project objective Hide the project objective Objective Neural progenitor cells undergo tens of thousands of cell divisions to generate the 80 billion neurons in a human brain. In neural progenitor cells, replication stress can lead to recurrent DNA break clusters (RDCs). Joining of two RDC breaks may introduce somatic genomic diversity. On the other hand, unbalanced genomic mosaicism in neural progenitor cells may lead to brain cancer and neuropsychiatric disorders. This proposal will test whether cell-autonomous DNA lesions that accumulate during rapid progenitor division contribute to the genetic heterogeneity found across neuronal cell populations. Aim 1 will elucidate how replication stress drives recurrent break clusters in the neural progenitor cell genome. We will evaluate whether chromatin loop extrusion mechanistically contributes to breakage repairs, and thus helps shape genomic structure variations. Aim 2 will quantify the extent and impact of tissue-specific recurrent break clusters in the embryonic brain. I will create a mouse model to identify DNA breaks in temporal and cell-type-specific manner across the entire population of neuronal progenitor cells. Aim 3 will evaluate whether replicative stress drives the recurrent genomic alteration in the RDC-containing gene during embryonic neurogenesis. We will investigate one of the RDC-containing gene Neurexin 1, where deletion or truncation results in neurological disorders. By combining a powerful in vitro cell line-based tool, versatile in vivo mouse models, and cutting-edge multi-omics approaches, we will uncover the mechanisms that are critical to the fields of genomics and developmental neuroscience and may also provide valuable new insights into neuropsychiatric disorders and tumor biology. Fields of science natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologymedical and health sciencesbasic medicineneurologynatural sciencesbiological sciencesgeneticsgenomes Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2020-STG - ERC STARTING GRANTS Call for proposal ERC-2020-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Coordinator DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG Net EU contribution € 1 500 000,00 Address Im neuenheimer feld 280 69120 Heidelberg Germany See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG Germany Net EU contribution € 1 500 000,00 Address Im neuenheimer feld 280 69120 Heidelberg See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
