Project Details
Projekt
Mechanistic Insights how the Direct Interactions of Proteins Involved in DNA Methylation Dynamics Impact Neuronal Differentiation
Applicants
Professor Dr. Albert Jeltsch; Professor Dr. Stylianos Michalakis; Professorin Dr. Franziska Traube
Subject Area
Biochemistry
Cell Biology
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 563452213
Methylation of the DNA base cytosine produces 5-methylcytosine (5mC), the most common epigenetic DNA modification in mammals. The DNA methyltransferase DNMT3A is the most important enzyme in neurons for de novo generation of 5mC from unmodified genomic cytosine. Elimination of 5mC occurs by oxidation to 5-hydroxymethylcytosine (5hmC) by alpha-ketoglutarate-dependent DNA dioxygenases, in neurons mainly by the TET3 enzyme. Methyl-CpG-binding protein 2 (MECP2) is a neuronal transcriptional regulator that can specifically bind both 5mC and 5hmC. All three proteins, DNMT3A, TET3 and MECP2, are highly expressed in neurons and are central to proper neuronal development and brain function. Dysfunction of any of these methylation writer, reader and eraser proteins are associated with severe neurodevelopmental disorders such as Rett syndrome, Beck-Fahrner syndrome or Tatton-Brown-Rahman syndrome. We have previously reported that MECP2 is an interaction partner of DNMT3A, and we have also discovered an interaction of MECP2 with TET3 in differentiating neurons. In the proposed project, we now aim to gain mechanistic insights into the interplay of DNMT3A, TET3 and MECP2 (Objective 1), elucidate the effects of DNMT3A, TET3 and MECP2 on chromatin adaptation and transcriptional processes in neuronal cells (Objective 2), and understand the immediate and long-term effects of their interplay on neuronal differentiation, maturation and function (Objective 3). Our mechanistic insights into the function and interaction of the three epigenetic proteins of interest will deepen our understanding of normal neural development and pathogenesis of the respective neuronal developmental disorders.
DFG Programme
Priority Programmes
