Control of Nervous System Maintenance and Regeneration by Chromatin Remodeling
Our group investigates how chromatin-remodeling enzymes including histone deacetylases (HDACs) and demethylases (HDMs) control the maintenance and regeneration of the nervous system. Our work is focused on the functions of myelinating cells (Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system) in these processes.
HDACs and HDMs are key epigenetic regulators that modify chromatin architecture by deacetylating and demethylating histones, respectively. In addition, HDACs deacetylate and thereby modulate the activity of many transcription factors. These enzymes are thus very powerful transcriptional regulators controlling gene activity at different levels.
We have shown that HDAC1 and HDAC2, two members of the large HDAC family of enzymes, control the development of Schwann cells, from specification (Jacob et al., Journal of Neuroscience, 2014) to terminal differentiation (Jacob et al., Nature Neuroscience, 2011). Chromatin remodeling is thus critical for the development of the nervous system (reviewed in Jacob et al., Molecular Neurobiology, 2011; Pattaroni and Jacob, Molecular Neurobiology, 2013; Jacob, Glia, 2015; Jacob, Current Opinion in Neurobiology, 2017).
Compared to development, the functions of chromatin remodeling in the maintenance and regeneration of the nervous system are not well known. The work of our group tackles these topics and compares the essential functions of chromatin-remodeling enzymes in Schwann cells and oligodendrocytes during these processes.
We recently demonstrated that HDAC1 and HDAC2 are necessary to maintain the integrity of the peripheral nervous system in adults (Brügger et al., PLOS Biology, 2015) and are critically involved in the control of regeneration after a nerve injury (Brügger et al., Nature Communications, 2017).
We are now investigating how to promote maintenance and regeneration of the peripheral and central nervous systems using chromatin-remodeling enzymes and use our scientific discoveries for translational studies in mice. Unravelling fundamental regulatory mechanisms that control development, maintenance and regeneration of the nervous system will help in designing novel therapeutic strategies for neurodevelopmental disorders, neurodegenerative diseases and regeneration of the nervous system after injury.
To reach our specific aims, we combine a wide range of in-vivo and in-vitro approaches: we use mouse genetics, behavioral analyses, molecular and cellular biology, in-vivo and in-vitro delivery of viral vectors, various imaging techniques including electron microscopy, confocal microscopy, high-resolution live-cell imaging at the single-cell level and 4-D reconstruction, biochemistry, mass spectrometry analyses, RNA-seq and ChIP-seq. In addition, we have set up an innovative model of nerve lesion using microfluidics to study the regeneration of the nervous system in vitro. We use this model to challenge our hypotheses and select the most promising strategies to test in vivo to enhance regeneration of the peripheral and central nervous systems in the context of disease or injury.