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Safeguarding Cell Fate by Terminal Repression during Development and Disease

Project description

Cell identity regulators in development and disease

Molecular master regulators that activate gene networks during development are well characterised, whereas the mechanisms that terminally repress alternative cell fates and determine cell identity and function remain poorly understood. The EU-funded SafeFate project will demonstrate that active terminal repression is a universal mechanism determining cell identity. A recent discovery by the team showed that the neuron-specific transcription repressor Myt1l is essential for neuronal cell identity as it represses non-neuronal programmes in neurons. SafeFate investigates if there is a distinctive class of terminal repressors that prevent alternative lineages from developing. Ultimately, the project aims to understand how to fight diseases associated with loss of cell identity and to reprogram cells for regenerative medicine.

Objective

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.

Host institution

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Net EU contribution
€ 1 761 489,00
Address
IM NEUENHEIMER FELD 280
69120 Heidelberg
Germany

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Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Research Organisations
Links
Total cost
€ 1 761 489,00

Beneficiaries (1)