The Polycomb Pathway in Myelin Maintenance and Repair of Peripheral Nerves.

摘要

Schwann cells produce myelin that insulates axons for rapid impulse conduction and ensheath both myelinated and unmyelinated axons to achieve stability of peripheral nerves. In addition, Schwann cells quickly transform into repair cells in response to nerve injury, and play diverse roles essential for regeneration. The work presented here describes that the regulation of chromatin environment by polycomb group proteins is required for peripheral nerve maintenance, and injury responsive reversal of polycomb silencing is involved in reprogramming Schwann cells for nerve repair.;The polycomb proteins form multimeric complexes, termed polycomb repressive complex 2 (PRC2) and PRC1, and create a transcriptionally repressive environment by catalyzing di- and tri-methylation of histone H3 at Lys27 (H3K27me2, -me3) and ubiquitination of histone H2A at Lys119 (H2AK119ub1). By employing genome wide mapping of H3K27me3 of peripheral nerves and a Schwann cell-specific deletion of a PRC2 component, my studies demonstrated that H3K27me3-mediated gene repression controls thickness of myelin sheath and maintains axon ensheathment. In the absence of the PRC2 subunit Eed, peripheral nerves exhibited age-associated defects in myelinated fibers, including hypermyelination and abnormal myelin folding, and defective ensheathment of unmyelinated axons by Schwann cells with axonal loss. These abnormalities are similar to abnormalities found in nerves affected by peripheral neuropathies such as hereditary neuropathy with liability to pressure palsies and malignant peripheral nerve sheath tumors, respectively. Interestingly, loss of H3K27me3 by the Schwann cell-specific Eed deletion in intact nerves was accompanied with upregulation of genes that normally become activated in response to injury, including genes encoding Schwann cell-derived NRG1, essential for efficient remyelination, and brain- and glial cell-derived neurotrophic factors BDNF and GDNF that promote neuronal survival. The findings raised a hypothesis that injury induces demethylation of H3K27 that mediates activation of such genes. Using models of peripheral nerve injury and nerve explant, I demonstrated that loss of H3K27me3 after injury is required and a rate limiting step in the activation of polycomb-repressed genes of injury. Taken together, my research identified that an epigenomic pathway mediated by H3K27me3 establishes long term peripheral nerve maintenance, and that gene activation after injury requires reversal of polycomb repression.