Institute of Biology II
 >> Functional Epigenetics in the animal model

Functional Epigenetics in the animal model

Research: Epigenetic regulation of neuronal physiology in the developing and adult brain 

The research of the department focusses on epigenetic gene regulation that determines cell fate determination and discrete neurophysiological processes underlying brain development and adult neuronal function in disease-related contexts. 

Epigenetic control emerges as a highly dynamic process on top of transcriptional networks governing diverse biological functions in development, aging and disease. We aim 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, with the ultimate goal 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.  We are specialized on diverse in vivo and in vitro transfection techniques, and make use of sophisticated microscopic systems and Life Cell Imaging

 

Projects:

  • 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 a critical step. For this we use different stage-specific conditional KO 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. We investigate the DNMT1-dependent regulation of discrete subcellular processes like endocytosis, thereby acting on neurons' physiology and cellular memory. We are further interested in how environmental stimuli affect the epigenomic DNMT1-dependent configurations.

    • 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.

    • Single-cell based transcriptome and methylation analysis of neurons

    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.

     

    Teaching:

    Research Practical: Epigenetics (8 SWS)RWTH Online
    Seminar Research Practical: Epigenetics (2 SWS)
    RWTH Online
     
    Flexible timing, if interested, please ask for free slots per email.

    Lecture and seminar: Epigenetics (4 SWS)(SS – wed 9-12 am) RWTH Online
    Practical: Epigenetics (8 SWS)(SS – September)    RWTH Online

     

    Team:

    Prof. Dr. Geraldine Zimmer-Bensch
    Short CV
    Team Leader
    Room: 0.111
    Phone: +49 (0)241-8024844
    Email: zimmer@bio2.rwth-aachen.de

    Dr. Daniel Pensold
    Post-Doc
    Room: 0.142
    Phone: +49 (0)241-8024864
    Email: pensold@bio2.rwth-aachen.de

    Andrzej Steckiewicz
    Biological-technical assistant
    Room: 0.142
    Phone: +49 (0)241-8020843
    Email: andrzej@bio2.rwth-aachen.de

    Cathrin Bayer
    PhD Student
    Room: 0.142
    Phone: +49 (0)241-8024864

    Annalena Dobbert
    Master Student
    Room: 0.142
    Phone: +49 (0)241-8024864
    Email: annalena.dobbert@rwth-aachen.de

    Lisanne Jente
    Student Researcher
    Room: 0.142
    Email: lisanne.jente@rwth-aachen.de

    10 most important publications:

    Symmank J, Bayer C, Schmidt C, Hahn A, Pensold D and Zimmer-Bensch G (2018) DNMT1 modulates interneuron morphology by regulating Pak6 expression through crosstalk with histone modification. Epigenetics. 2018;13(5):536-556. (IF 4.9) (PubMed)

    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. (IF 6.6) (PubMed) 

    Zimmer-Bensch G (2018) Diverse facets of cortical interneuron migration regulation-Implications of neuronal activity and epigenetics; Brain Research Dec 1;1700:160-169. (IF 3.1) (PubMed)  

    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 (2017) 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. (IF 6.9) (PubMed

    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. (IF 6.1) (PubMed

    Beetz C, Koch N, Khundadze M, Zimmer G, Nietzsche S, Hertel N, Huebner A, Mumtaz R, Schweizer M, Dirren E, Karle E, Irintchev A, Alvarez V, Redies C, Westermann M, Kurth I, Deufel T, Kessels M, Qualmann B, Hübner C (2014) A spastic paraplegia mouse model reveals REEP1-dependent ER shaping. J Clin Invest 124(6):2809. (IF 12.8) (PubMed

    Rüdiger T, Zimmer G, Bachmann S, Castellini V, Bagnard D and Bolz J (2012) Integration of opposing semaphoring guidance cues in cortical axons. Cereb Cortex 23 (3):604-14. (IF 8.3) (PubMed) 

    Zimmer G, Rudolph J, Landmann J, Gerstmann K, Steinecke A, Gampe C, Bolz J (2011) Bidirectional ephrinB3/EphA4 signaling mediates the segregation of MGE-and POA derived interneurons in the deep and superficial migratory stream. J Neurosci 31:18364-18380. (IF 7.8) (PubMed) 

    Zimmer G, Schanuel SM, Burger S, Weth F, Steinecke A, Bolz J, Lent R (2010) Chondroitin sulfate acts in concert with semaphorin 3A to guide tangential migration of cortical interneurons in the ventral telencephalon. Cereb Cortex (10):2411-22. (IF 6.9) (PubMed) 

    Zimmer G, Kästner B, Weth F, Bolz J (2007) Multiple effects of ephrin-A5 on cortical neurons are mediated by SRC family kinases. J Neurosci 27:5643-5653. (IF 7.8) (PubMed