Functional Epigenetics in the animal model
Dynamics of epigenetic regulation in brain development and function with implications in associated disease and age-related neurodegeneration
Epigenetic transcriptional control emerges as a highly dynamic process on top of transcriptional networks governing diverse biological functions in development, aging and disease. The research focus of the department is to decipher cell type-, stage- and context-specific actions of DNA methyltransferases executing DNA methylation, as well as their crosstalk with histone modifying mechanisms in the brain, to approach disease- and age-related questions and to open new avenues for the establishment of epigenetic-based therapies. To this end, we apply highly innovative techniques such as sequencing-based single cell and global transcriptome analysis, as well as global and site-specific methylation analysis in addition to chromatin-immunoprecipitation. For translational research we work with animal models in addition to cell and primary cultures.
1. Epigenetics in appetite regulation
The release of the inhibitory transmitter GABA has been associated with appetite regulation in the cortex and hypothalamus, and defects in hypothalamic circuits are involved in obesity. Obesity is a life style disease affecting a continuously increasing number of individuals, especially children, which comes with several secondary diseases. Aberrant epigenetic regulation appears crucially involved in the pathology of obesity. We found that the conditional deletion of a key epigenetic regulator in inhibitory GABAergic interneurons of the cortex and hypothalamus caused an obese phenotype in mice. Preliminary data point to elevated GABAergic transmission due to changes in endocytic-based vesicle recycling in knockout mice. Within the scope of this project, the PhD student will decipher the epigenetic networks of central nervous-based appetite regulation at cellular, subcellular and systemic level.
2. Epigenetics in the development and function of the cortical GABAergic system
Deficits in the function of inhibitory GABAergic interneurons of the cerebral cortex are implicated in the pathophysiology of schizophrenia, major depressive disorder, bipolar disorder, Alzheimer's disease and Parkinson's disease. Such defects in part rely on defective development, of which the migration from sites of origin to the cortical targets represent as critical step. For this we use different stage-specific conditional mouse models to approach the function and mode of action of the DNA methyltransferase 1 during interneuron development with focus on migration, as well as in sustaining adult interneuron functionality. As epigenetic remodeling seems associated with age-related structural and functional changes of the nervous system, we further investigate the implication of epigenetic alterations in neuronal aging.
3. Single-cell based transcriptome and methylation analysis
The brain consists of diverse neuronal and non-neuronal cell-types which are distinctively affected by aging and disease. Besides the question of how such a diversity of cells are generated during development, responding differently to environmental cues and cell-type-specifically integrate in neuronal circuits, it is still a matter of debate, why some cell types are more vulnerable than others towards aging or disease-causing conditions.
To approach such questions, single-cell based sequencing approaches are required to dissect the epigenetic and transcriptional networks in diverse cell types, which is a current focus of our work.
Prof. Dr. Geraldine Zimmer-Bensch
Phone: +49 (0)241-8020844
Dr. Daniel Pensold
Phone: +49 (0)241-8024864
Phone: +49 (0)241-8020843
Phone: +49 (0)241-8020863
Phone: +49 (0)241-8024856
1. Symmank J, Bayer C, Schmidt C, Hahn A, Pensold D and Zimmer G (2018) DNMT1 modulates interneuron morphology by regulating Pak6 expression through crosstalk with histone modifications. Epigenetics 2018 Jun 18.
2. Symmank J, Gölling V, Gerstmann K and Zimmer G (2018) The Transcription Factor LHX1 Regulates the Survival and Directed Migration of POA-derived Cortical Interneurons. Cereb Cor 2018 Apr 18.
3. Pensold D, Zimmer G (2018) Single cell transcriptomics reveals regulators of neuronal migration and maturation during brain development. Journal of Experimental Neuroscience 2018 Mar 8;12.
4. Symmank J, Zimmer G (2017) Regulation of neuronal survival by DNA-Methyltransferases. Neural Regen Res 12(11):1768-1775.
5. Pensold D, Symmank J, Hahn A, Lingner T, Salinas-Riester G, Donnie B, Ludewig F, Rotzsch A, Haag N, Andreas N, Schubert K, Hübner C, Pieler T, Zimmer G (2016) The DNA Methyltransferase 1 (DNMT1) Controls the Shape and Dynamics of Migrating POA- Derived Interneurons Fated for the Murine Cerebral Cortex. Cereb Cor 27:5696-5714.
6. Gerstmann K, Pensold D, Symmank J, Khundadze M, Hübner Ch, Bolz J, Zimmer G (2015) Thalamic afferents influence cortical progenitors via ephrinA5/EphA4 interactions. Development 142:140-150.