Gene Expression & Regulation
Gene expression is tightly regulated to integrate protein functions into cellular metabolism and signalling processes. Mammalian cells possess two genetic systems, based on the nuclear genome and that of the mitochondria. The latter is particularly relevant in excitable cells of the cardiac and nervous systems, which rely on a highly efficient energy metabolism that is ensured by accurate mitochondria homeostasis. However, mitochondrial gene expression is still poorly understood. Line of Research 1 addresses gene expression in these two different cellular compartments.
RA 1.1 investigates the principles of mitochondrial gene expression. The goal is to understand the mechanisms of mitochondrial transcription and translation and to investigate whether and how these processes are physically linked, spatially organized, and functionally interconnected. RA 1.2 focusses on epigenetic and epitranscriptomic processes in cardiomyocytes and neuronal cells, i.e. in postmitotic cells, through which transient stimuli can be transformed into long-term adaptive changes of the cardiac and nervous systems, and which are involved in neurodegeneration and heart failure. We will identify and characterize writers, readers, and erasers of chromatin and RNA modifications. For example, we will analyse the effects of chromatin modifications and RNA methylation on transcriptome plasticity, and we will define mitochondrial translational plasticity in the context of membrane-bound translation processes. RA 1.3 investigates the process of "proteostasis", which ensures the maintenance of a healthy proteome through correct protein folding and targeting. Of particular medical relevance are age-related degenerative misfoldings, which cause neurological and cardiac diseases and represent a research focus of RA 1.3.
All RAs aim to develop pharmacological therapies to target gene expression.
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Multiscale approaches to heart and brain
A central pillar of our efforts is the development and application of techniques that enable scientists to model heart and brain tissues theoretically and interrogate these systems experimentally. Within the cluster of excellence, we enormously benefit from the multidisciplinarity and the cross-fertilization between groups of different backgrounds and interests.
Therefore, this line of research was established to facilitate the interaction between the methods developers and the users: instruments are developed to empower biologists to do novel experiments while new methods can be readily applied and tested in labs and clinics.
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Nanodomains for Excitability
One prominent example of membrane protein assemblies in excitable cells is the Ca2+ channel cluster. The organization and function of this nanoscale functional unit, and the ensuing cell contraction or Ca2+-triggered membrane fusion, will be targeted in NANODOMAINS FOR EXCITABILITY. Here we study voltage-gated Ca2+ channels (CaV) and ryanodine receptors (RyR, Ca2+-release channels of the endoplasmic reticulum) in sensory hair cells and atrial cardiomyocytes. Both cell types use CaV1.3 and RyR2 for generating cytosolic Ca2+ signals that regulate Ca2+-dependent effector functions such as contraction or membrane fusion. Genetic defects affecting these two channel types cause neurocardiac disorders, such as deafness and sinoatrial dysfunction in SANDD syndrome (CaV1.3), as well as arrhythmia and epilepsy (RyR2). MBExC will use converging bottom-up and top-down approaches to comparatively study the assembly, function, and dysfunction of CaV1.3 and RyR2, both in simple expression systems and in their native environment in hair cells and cardiomyocytes. Moreover, we will develop virus-mediated gene replacement targeting components of the CaV1.3 and RyR2 complexes as a therapeutic strategy. Virus-mediated gene replacement and genome editing will also be targeted at ferlin-based Ca2+-triggered membrane fusion. Ferlins, multi-C2-domain proteins, are essential for synaptic vesicle exocytosis in hair cells (otoferlin) and for plasma membrane resealing and T-tubule remodelling in cardiomyocytes (dysferlin). Genetic defects cause deafness (otoferlin) and cardiomyopathy (dysferlin). Building on the long-standing expertise at the Göttingen Campus in neuronal Ca2+-triggered membrane fusion, we now set out to elucidate the fusion machineries of hair cells and cardiomyocytes and we will develop genetic approaches to restore normal function in ferlin-related diseases.
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