Analysis of the distinct regulatory functions of DNA methylation in memory-related gene expression

• Applicant: Professorin Dr. Ana M. M. Oliveira
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 250202559

An essential step for memory formation is gene transcription activation. The regulation of transcription is critical for the achievement of proper expression of the memory related genes. The methylation of DNA has been proposed as a key mediator in this process. DNA methyltransferase proteins (Dnmts) are responsible for the writing of methylation marks and the methyl-binding proteins (such as MeCP2) for reading and translating this marks into changes in chromatin structure and accessibility for transcription. The precise mechanism by which DNA methylation regulates transcription during memory formation is far from being understood. This proposal describes a research program that aims at further investigating this question.In my previous work I found that the levels of Dnmt3a2 and Dnmt3b are regulated by neuronal activity - Dnmt3a2 is upregulated, whereas Dnmt3b is downregulated - that Dnmt3a2, is required for memory formation and regulates the expression of memory related genes in a positive manner. Moreover, I showed that the basal and learning-induced expression of Dnmt3a2 is impaired in the aging hippocampus and that this is causally linked with aging-dependent cognitive decline.I now propose a novel concept in the regulation of gene expression by DNA methylation. I hypothesize that Dnmt3b functions as a memory suppressor gene, which expression needs to be repressed during memory consolidation for the optimal expression of memory related genes. This hypothesis will be experimentally validated by assessing the effect of the modulation of Dnmt3b levels in memory formation. Moreover, I propose that the fine-tuning of memory related gene expression is achieved via an intermediate step, the regulation of expression of relevant miRNAs by Dnmt3a2. Thus, I provide a mechanism through which a single gene can modulate the expression of several mRNAs. My preliminary work identified a list of putative Dnmt3a2 target miRNAs (DTMs). I now propose a set of experiments (combination of molecular and behavioral approaches) that will allow assessing whether the regulation of expression of DTMs plays a role in memory formation. The DNA methylation marks are catalyzed by Dnmts whereas the interpretation of the methylation pattern is performed by the methyl binding proteins that include MeCP2. Therefore MeCP2 translates methylation marks into functional changes. I propose that the DNA occupancy by MeCP2 constitutes another level critical for the regulation of gene expression in the mature brain. In line with this hypothesis, I will test whether hippocampal MeCP2 is required for memory formation in adult mice and whether MeCP2 genomic occupancy changes with aging and the subsequent impact on gene expression.This study will provide new, fundamental insights into the mechanism of gene expression regulation in memory formation. It will also lead to the identification of novel candidates for the development of therapies for aging-related diseases.

• DFG Programme: Independent Junior Research Groups
• Participating Person: Professor Dr. Frank Lyko