Descrizione del progetto
I regolatori dell’identità cellulare nell’ambito dello sviluppo e della malattia
I regolatori molecolari principali che attivano le reti geniche durante lo sviluppo sono ben caratterizzati, mentre restano scarsamente compresi i meccanismi che reprimono in modo terminale i destini cellulari alternativi e determinano l’identità e la funzione delle cellule. Il progetto SafeFate, finanziato dall’UE, dimostrerà che la repressione terminale attiva è un meccanismo universale che determina l’identità delle cellule. Una scoperta recente del gruppo di ricercatori ha dimostrato che il repressore di trascrizione neurone-specifico Myt1l è essenziale per l’identità delle cellule neuronali, in quanto reprime i programmi non neuronali dei neuroni. SafeFate indaga sull’esistenza di una classe distintiva di repressori terminali che impedisce lo sviluppo di lignaggi alternativi. In definitiva, il progetto è volto a comprendere il modo in cui combattere le malattie correlate alla perdita di identità cellulare e riprogrammare le cellule per la medicina rigenerativa.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
69120 Heidelberg
Germania