New funded project

New collaboration project of the Jeltsch and Traube groups

5-methylcytosine (5mC) is the most abundant epigenetic DNA modification in mammals. In neurons, the DNA methyltransferase DNMT3A is the principal enzyme responsible for  de novo 5mC establishment. Removal of 5mC occurs through oxidation to 5-hydroxymethylcytosine (5hmC), mediated mainly by the α-ketoglutarate–dependent dioxygenase TET3. The transcriptional regulator MECP2 binds both 5mC and 5hmC and plays a central role in neuronal gene regulation. All these proteins are highly expressed in neurons and are essential for normal neuronal development and brain function. Disruption of these epigenetic writer, eraser, and reader proteins causes severe neurodevelopmental disorders, including Tatton-Brown-Rahman syndrome (DNMT3A misfunction), Beck-Fahrner syndrome (TET3 misfunction), and Rett syndrome (MECP2 misfunction). In a new collaboration project of the Jeltsch and Traube groups, together with the group of Prof. Dr. Stylianos Michalakis at LMU Munich, aim to provide novel insights into the impact of the direct interactions of these proteins on neuronal differentiation. We previously reported an interaction between MECP2 and DNMT3A, and more recently discovered that MECP2 also interacts with TET3 in differentiating neurons. Building on these findings, our project aims to (1) dissect the mechanistic interplay of DNMT3A, TET3, and MECP2, (2) define their roles in chromatin remodeling and transcriptional regulation in neuronal cells, and (3) determine how their interactions influence neuronal differentiation, maturation, and function over time. By elucidating the coordinated functions of these epigenetic regulators during neuronal development, we seek to advance our understanding of both normal neural development and the molecular basis of related neurodevelopmental disorders. The project is funded by the DFG in the context of SPP 2502 Epiadapt “ Epigenomic adaptations of the developing neural chromatin”.