Descripción del proyecto
Contribución de las roturas de ADN a la heterogeneidad genética de las neuronas
Las células progenitoras neurales sufren decenas de miles de divisiones para generar los miles de millones de neuronas del encéfalo humano. Este estrés de replicación puede conducir a grupos de ruptura de ADN recurrentes y crear así la diversidad genómica somática. El desequilibrado mosaico genómico de las células progenitoras neurales puede originar cáncer cerebral y trastornos neuropsiquiátricos. El proyecto financiado con fondos europeos BrainBreaks pretende investigar si las lesiones en el ADN, producidas durante la división de las células progenitoras, contribuyen a la heterogeneidad genética de las neuronas. Los investigadores utilizarán herramientas basadas en líneas celulares «in vitro», modelos murinos «in vivo» y enfoques multiómicos de vanguardia para desvelar los mecanismos genómicos que proporcionarán nueva información valiosa sobre los trastornos neuropsiquiátricos y la biología tumoral.
Objetivo
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.
Ámbito científico
Not validated
Not validated
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
69120 Heidelberg
Alemania