Non-canonical cytosolic function of the DNA methyltransferase 1 in regulating the morphology of developing cortical neurons

• Applicant: Professorin Dr. Geraldine Zimmer-Bensch
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551149509

Epigenetic mechanisms such as histone modifications and DNA methylation are pivotal for proper cortical development. Mutations in genes coding for writers of epigenetic marks are associated with a diverse spectrum of neurodevelopmental malformations and neurological diseases. DNA methyltransferase 1 (DNMT1), the largest member of the DNMT family, is known for its role in modulating various aspects of neuronal development as well as adult brain function through canonical and non-canonical actions. DNMT1 modulates gene transcription DNA methylation-dependently as well as through a crosstalk with histone modifications. In line with the functional diversity of DNMT1, different mutations in the DNMT1 gene are related with a variety of neurological symptoms. Of note, DNMT1 harbors the largest N-terminal domain of all DNMTs that provides multiple interaction sites with diverse proteins, enabling this functional diversity. Alike other nuclear proteins, DNMT1 has been observed in the cytosol, whereas discrete cytosolic functions have not been described yet. Surprisingly, we found numerous cytosolic proteins to interact with DNMT1, one of which was DOCK7. Both proteins elicit similar effects on cortical neuron morphology and microtubule dependent trafficking. For this, the suggested study will explore the involvement of DNMT1 in cytosolic processes focusing on its interaction with DOCK7, a known regulator of microtubule dynamics and neuronal morphology. This interaction is hypothesized to facilitate DOCK7's role in cytoskeletal remodeling, potentially through mechanisms of activation or scaffolding that involve additional proteins and kinases. By a combination of a diverse spectrum of in vivo and in vitro wet-lab with computational simulation approaches, this proposal aims to delineate the unconventional role of DNMT1 in cytosolic interactions with DOCK7, investigating how this complex influences the morphological maturation of cortical neurons and the underlying intracellular processes. In sum, this proposal aims to address a completely unexplored role of cytosolic DNMT1 in neuronal development. This study not only illuminates the diverse functional spectrum of DNMT1 but also underscores its potential impact on disease phenotypes linked to specific DNMT1 mutations.

• DFG Programme: Research Grants