Control of Nervous System Maintenance and Regeneration by Chromatin Remodeling Enzymes
Our group investigates how chromatin-remodeling enzymes including histone deacetylases (HDACs) and demethylases (HDMs) control the maintenance and regeneration of the nervous system after an injury. Our work is focused on the functions of myelinating cells, Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS), 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 other types of proteins including 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 class I HDACs, control the development of Schwann cells, from specification (Jacob et al., J. Neurosci., 2014) to terminal differentiation (Jacob et al., Nat. Neurosci., 2011). The work of our group is now focused on the functions of chromatin remodeling enzymes in the maintenance and regeneration of the nervous system. We showed that HDAC1 and HDAC2 are necessary to maintain the integrity of the PNS in adults (Brügger et al., PLOS Biol, 2015), and that they slow down axonal regrowth after lesion but are required for remyelination of regenerated axons (Brügger et al., Nat. Commun., 2017). HDAC1 and HDAC2 are however critical for remyelination of the PNS after a traumatic injury and of the CNS after a demyelinating lesion such as in the case of the neurodegenerative disease multiple sclerosis (Duman et al., Nat. Commun., 2020). In this latter study, we also show that increasing HDAC2 activity promotes remyelination in young and old adults, which could help to foster the regeneration of lesions due to trauma or a neurodegenerative disease such as multiple sclerosis.
Remyelinated spinal cord after a demyelinating lesion
Another HDAC interesting to target is HDAC8. We showed that after a traumatic injury, HDAC8 negatively regulates the repair process specifically in Schwann cells interacting with sensory neurons. In the absence of HDAC8, sensory neurons regrow faster and the sensory function is also recovered faster (Hertzog et al., Nat. Commun., 2025). This work opens future avenues of treatment in the context of peripheral nerve injuries and potentially also peripheral neuropathies. We are continuing our research on this topic.
The PNS can often efficiently regenerate after a lesion, whereas regeneration in the CNS is not efficient. This is to a large extent due to the presence of different types of glial cells in these two systems. Indeed, Schwann cells in the PNS promote axonal regeneration after lesion, whereas oligodendrocytes in the CNS and the formation of a glial scar prevent axonal regrowth. Our group compares the essential functions of chromatin-remodeling enzymes in Schwann cells and oligodendrocytes to better understand how Schwann cells promote axonal regeneration and to use this new knowledge to induce regeneration in the CNS. For this work, we have set up lesion models using microfluidics. With these models, we identified a previously unknown behavior of Schwann cells that occurs early after an axonal lesion: we showed that Schwann cells build actin spheres to induce the disintegration of the damaged part of the axons after lesion, which accelerates the regrowth of the surviving axons. By elucidating the mechanism of action underlying this behavior, we were able to transfer this behavior to oligodendrocytes, which promoted axonal regrowth after lesion (Vaquié et al., Cell Reports, 2019). This model also allowed us to identify the phosphatase Dusp6 as a key negative regulator of the repair phenotype in oligodendrocytes. Indeed, in the absence of Dusp6, oligodendrocytes acquire some repair capacities similar to Repair Schwann cells (Nocera et al., bioRxiv, 2023). Upon receiving approval for our last experiments to finish this study, we will be happy to share it in full with the scientific community and the public.
We are continuing to use our lesion models to identify other potential mechanisms that could increase the plasticity of the PNS and CNS. We use these discoveries to test exploratory treatments in vivo to improve the maintenance of integrity of the nervous system in young and old adults and its regeneration after injury. The aims of our work are thus to unravel basic mechanisms of cell plasticity and help in designing novel therapeutic strategies for neurodegenerative diseases and regeneration of the nervous system after injury.
To reach our aims, We combine a wide range of in vtro and in vivo approaches: we use genetics, behavioral analyses, molecular and cellular biology, viral vectors, classic and advanced imaging techniques including high-resolution live-cell imaging at the single-cell level and 4D reconstruction, electron microscopy, biochemistry, proteomics, transcriptomics, and epigenomics.
Interactive Biomaterials for Neural Regeneration (InteReg)
is a new interdisciplinary and very exciting line of research that we have officially started last year with the generous funding scheme "Breakthroughs" from the Carl Zeiss-Stitfung. With InteReg, we are bridging the worlds of Neuroscience and Soft Biomaterials and we are creating solutions for the repair of the CNS after a traumatic injury or in the context of a neurodegenerative disease such as multiple sclerosis. To know more about this project, follow us on our InteReg website.