Descripción del proyecto
Los reguladores de la identidad celular en el desarrollo y la enfermedad
Los reguladores moleculares principales que activan las redes de genes durante el desarrollo se han caracterizado adecuadamente, mientras que los mecanismos que reprimen al final los destinos celulares y determinan la identidad y la función de las células todavía no se comprenden bien. El proyecto financiado con fondos europeos SafeFate demostrará que la represión final activa es un mecanismo universal que determina la identidad celular. Un descubrimiento reciente realizado por el equipo mostró que el represor de la transcripción específico de neuronas Myt1l es fundamental para la identidad de las células neuronales ya que reprime los programas no neuronales en las neuronas. SafeFate investiga si existe una clase distintiva de represores finales que impiden el desarrollo de linajes alternativos. En última instancia, el proyecto tiene como objetivo comprender la forma de combatir enfermedades relacionadas con la pérdida de identidad celular y de reprogramar las células para la medicina regenerativa.
Objetivo
Cell identity and function requires both induction of desired genes and repression of unwanted programs. While master regulators that activate gene networks during development are well characterized, the mechanisms that terminally repress alternative fates remain poorly understood. Within this project, I aim to demonstrate that active terminal repression is a universal mechanism required to prevent loss of cell identity and disease.
We recently found that the neuron-specific transcription repressor Myt1l is essential to induce neuronal cell identity. Myt1l is expressed in virtually all neurons throughout life and its loss in mature neurons impairs neuronal gene expression and function, suggesting a role in maintaining cell fate. Unlike known repressors such as REST that specifically silences neuronal genes in non-neuronal cells, Myt1l represses many non-neuronal programs in neurons. I therefore propose that a new class of terminal repressor exists that continuously represses alternative lineages to confer and maintain cell identity.
Since Myt1l mutations often occur in autism and schizophrenia I will investigate how loss of terminal repression can contribute to these poorly understood but common mental disorders. This will require molecular and behavioural studies in human and mouse models. We will also investigate how a sequence specific terminal repressor biochemically interacts with general epigenetic machinery to continuously silence unwanted programs during neuronal reprogramming. Finally, we will test candidate terminal repressors in other lineages by loss and gain of function approaches to analyse whether terminal repression is a universal principle of biology. Ultimately this will provide insight into fighting diseases associated with loss of cell identity and to efficiently generate cells for regenerative medicine using reprogramming.
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ERC-STG - Starting GrantInstitución de acogida
69120 Heidelberg
Alemania