The role of the DNA Methyltransferase1 (DNMT1) in the development of somatostatin (SST)-positive cortical interneurons

• Applicant: Professorin Dr. Geraldine Zimmer-Bensch
• Subject Area: Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427999744

The spatial and temporal inhibitory actions of the enormously heterogeneously collection of GABAergic interneurons tremendously influence cortical information processing, which is reflected by diseases like autism, epilepsy and schizophrenia that involve defective cortical inhibition. Decrypting regulatory networks that direct subtype-specific cortical interneuron development is of great interest, as this helps to identify critical events implicated in the etiology of such diseases. Epigenetic mechanisms of gene regulation like DNA methylation executed by DNA methyltransferases (DNMTs) and histone modifications call increasing attention in sculpting developmental processes and human health. Several studies associate altered expression levels and function of the DNA methyltransferase 1 (DNMT1) in subsets of embryonic and adult cortical interneurons in patients diagnosed with schizophrenia. Although accumulating evidence supports the relevance of epigenetic signatures for instructing cell type-specific development, only very little is known about their functional implications in discrete developmental processes and in subtype-specific maturation of cortical interneurons.By single cell transcriptomics, global transcriptome and methylome analysis of FAC-sorted embryonic interneurons in combination with functional validation experiments, we have recently found that DNMT1 promotes the migration of interneurons originating in the preoptic area (POA) mainly through interactions with histone modifications.In contrast, preliminary experiments indicate that DNA methylating actions of DNMT1 seem crucial for the proper development of SST-positive interneurons, potentially involved in setting up transcriptional programs that direct the subtype-specific development. SST-interneurons are generated mainly in the MGE and have been shown to be affected in schizophrenia and in other human psychiatric and neurological disorders. Thus, we here aim to dissect the role of DNMT1 in the post-mitotic maturation of SST-positive interneurons. To this end, we will apply an innovative and diverse yet well-established collection of methods involving mouse genetics, high-throughput sequencing and functional bioassays. To determine the processes DNMT1 regulates during SST-interneuron maturation, a comprehensive phenotypic characterization of embryonic, postnatal and adult conditional DNMT1 wild-type and knockout mice will be conducted. Moreover, DNMT1-dependent remodeling in DNA methylation in migrating SST-interneurons will be revealed by sequencing-based analysis of FACS-enriched SST interneurons to map the global changes in DNA methylation and transcription upon Dnmt1 deletion.Decoding the DNMT1-dependent epigenetic reconfigurations SST interneurons adopt during their maturation helps to better understand subtype-specific developmental programs and might be of relevance for disease-related questions, opening new avenues for the establishment of epigenetic-based therapies.

• DFG Programme: Research Grants