Descripción del proyecto
Protección del genoma por las células germinales frente a los elementos transponibles
Los elementos transponibles (ET) forman parte natural de los genomas de mamíferos, pero cuando se activan pueden alterar la estabilidad del genoma. En el desarrollo fetal se pierde la metilación del ADN, que suele mantener en silencio los ET. Ello conduce a la reactivación potencial de los ET, lo que podría causar daños genéticos. Sigue sin estar claro cómo afrontan este reto las células germinales fetales, conocidas como prospermatogonias. Con el apoyo de las acciones Marie Skłodowska-Curie, el proyecto TE-Time responderá a esta pregunta. En concreto, estudiará los patrones de actividad de los genes y la organización tridimensional del genoma. Los investigadores esperan descubrir nuevos conocimientos sobre la regulación de los ET, con posibles aplicaciones para la infertilidad, el cáncer y otras enfermedades.
Objetivo
Mammalian genomes are filled with transposable elements (TEs), whose activity is usually silenced by DNA methylation. However, during the fetal phase of germline development, DNA methylation is naturally lost as part of the epigenetic reprogramming of the future gametes. This leads to the transcriptional activation of transposition-competent TEs, which normally represents a threat to genomic integrity and species fitness. How fetal male germ cells (a.k.a. prospermatogonia) mechanistically cope with TE reactivation and protect the integrity of the genetic material?
Preliminary data from the lab indicates that TEs acquire both permissive H3K4me3 and repressive H3K9me3 marks in mouse prospermatogonia, and may be subject to early transcription termination. I will investigate whether these regulatory patterns may allow prospermatogonia to tolerate active TEs and even integrate them into their own developmental program. Focusing on this unique cellular model provided by prospermatogonia, I will 1) assess the dynamics of H3K4me3-K9me3 marks using single cell multimodal chromatin profiling in relation to prospermatogonia development, 2) analyze TE transcriptional features, 3) study the 3D coordination of TE regulation within the nucleus and 4) investigate whether TEs participate to the prospermatogonia gene expression program by providing regulatory sequences. I believe this project will identify novel principles in TE regulation with immediate relevance for the field of reproductive biology. Knowledge will be gained regarding the origin of infertilities, but also for other pathological contexts such as cancer and neurodegenerative diseases, whereby DNA methylation loss and TE reactivation are commonly observed.
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
75231 Paris
Francia