Investigating the interplay of neuron-specific transcription factors and ubiquitous epigenetic regulators in safeguarding neuronal fate induction and maintenance —EpiSafeFate—

• Applicant: Dr. Moritz Mall
• Subject Area: Developmental Neurobiology ; General Genetics and Functional Genome Biology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563470499

Recent studies have underscored the importance of active gene repression, not just activation, in maintaining stable neuronal cell identities. While terminal selectors and their interactions with epigenetic co-activators are well-characterized for driving neuronal gene expression, comparatively little is known about how transcriptional repressors collaborate with repressive epigenetic machinery to silence unwanted gene programs lifelong. Contrary to the long-standing notion of stable epigenetic silencing, emerging evidence indicates that continuous, active repression is required to preserve the neuronal state, even after differentiation is complete. Age-associated alterations in neuronal gene expression have been linked to neurodegenerative diseases, suggesting that the stability of epigenetic repression may deteriorate over time. Our results show that MYT1L, a neuron-specific transcriptional repressor linked to brain disorders, interacts with repressive chromatin regulators (e.g., LSD1, HDAC) and is required to maintain neuronal fate and function in mature neurons in vivo. This interaction may be key to ensuring that non-neuronal or progenitor-like programs remain OFF, thus safeguarding neuronal identity and function across the lifespan. Investigating how repressive epigenetic complexes function in developing and mature–long-lived neurons by interaction with neuron-specific transcript factors can, therefore, provide unique insights into whether active repression is required to suppress unwanted plasticity and maintain neuronal identity. More generally, it will enable insights about the stability of cell fate and the role of active repression in this process. We will use induced human neurons and in vivo mouse models to address these questions, employing neuron-specific and developmentally timed Cre-mediated MYT1L deletions. By manipulating MYT1L and its interacting epigenetic modifiers at various stages of neuronal differentiation and maturation, we aim to identify how these factors cooperate to prevent fate destabilization. We have designed three complementary aims to uncover the mechanisms of active epigenetic repression in neurons, which aligns with the goals of the priority program EPIADAPT.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2502: EPIADAPT: Epigenomic adaptations of the developing neural chromatin