Metabolism-epigenetics crosstalk during direct neuronal reprogramming

• Applicant: Giacomo Masserdotti, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563470442

Direct neuronal reprogramming offers a promising approach to generate new neurons directly from differentiated non-neuronal cells, bypassing both proliferative and pluripotent states. Our recent research demonstrated that human astrocytes can be converted into functional neurons through the forced expression of the transcription factor Ngn2. Notably, treatment with nicotinamide riboside (NR), a precursor of NAD, significantly enhances neuronal generation. In this project, we aim to: 1) investigate the molecular mechanisms of human astrocyte-to-neuron direct conversion by integrating transcriptomic and epigenomic analyses at both single-cell and population levels over time. This will help identify the emergence of cells that fail to reprogram and characterize their associated epigenetic features; 2) examine how NR influences the conversion process by regulating nuclear NAD-dependent sirtuins and explore the role of NNMT-dependent homocysteine generation in modulating DNA methylation and, thus, neuronal reprogramming. Overall, this study will illuminate the interplay between metabolism and epigenetics during direct neuronal reprogramming. By unraveling these mechanisms, we aim to develop more precise and efficient strategies for cell-based replacement therapies to promote brain repair.

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