Project Details
Projekt
Allele-specific epigenetic regulation by Zfp57 in the control of neuronal identity and function during neuronal differentiation
Applicant
Dr. Sara Zocher
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 563470531
The proper generation of neurons from neural stem and progenitor cells (NSPCs) is crucial for brain development and function. During neuronal differentiation, NSPCs must silence stem cell specific-molecular programs while upregulating gene expression programs that define specific neuronal identities. Proper epigenetic regulation is essential to control this critical cell fate transition, and its dysregulation causes neurodevelopmental defects. However, the precise epigenetic mechanisms that establish and fine-tune neuron-specific gene expression programs during neurogenesis are still poorly understood. My previous studies revealed an essential role of the epigenetic mark DNA methylation in the generation of neuronal identity and function during hippocampal neurogenesis—a unique form of neuronal development enabling life-long brain adaptation, learning, and memory. Specifically, I showed that de novo DNA methylation of neuronal genes during neuronal differentiation is required for the upregulation of neuron-specific gene expression programs, for proper neuronal maturation and functional integration into the neural circuit. My further analyses suggested allele-specific DNA methylation, the deposition of methyl marks on only one of the parental alleles (known to be particularly prevalent in neurons), as a mechanism regulating gene dosage during neurogenesis, enabling particularly fine-tuned upregulation of neuronal gene expression programs. However, how allele-specific epigenetic patterns are established during neurogenesis and their functional implications for neuronal gene regulation and the generation of neuronal identity and neuronal function are unknown. My preliminary data suggest the genomic imprinting factor Zfp57 to be a key player controlling allele-specific DNA methylation and gene expression during neuronal differentiation. In this proposal, I will (i) characterize the dynamics of allele-specific DNA methylation during neurogenesis and analyze its causal role in driving gene expression changes associated with neuron formation, (ii) investigate the precise mechanism how the imprinting factor Zfp57 controls allele-specific epigenetic changes and neuronal gene expression during neurogenesis, and (iii) assess the requirement of Zfp57-mediated epigenetic regulation for the formation of functional new neurons, including their adaptation to environmental stimulation. The results of this proposal will reveal a new epigenetic mode governing neuronal differentiation and hence will provide fundamental insight into the gene regulatory mechanisms controlling brain development and function. Moreover, this proposal will shed light on the molecular basis of neurological disorders with parent-of-origin-specific phenotypes and will help to explain neurodevelopmental deficits observed in imprinting disorders.
DFG Programme
Priority Programmes
