Regulation of 3D genome organisation and function in axonal regeneration

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Injury in the central nervous system (CNS) such as spinal cord injury (SCI) results in severe neurological functional impairment and poor recovery due to failure in regeneration and re-connectivity of injured axons. To date, it is still unclear why nerves in the brain or spinal cord cannot regrow after injury. While it is known that many genes that could support the growth of nerves cannot be activated after injury, the reasons for this failure remain obscure. Recent accumulating evidence by others and us suggests that changes in the accessibility of genes that control the regeneration programme may facilitate repair and regeneration after spinal injury for example. Understanding how the regeneration programme is regulated could be very important to improve regeneration of nerves and recovery of function in people affected by nerve and spinal injuries.The regulation of gene expression is affected by the 3D structure of the chromatin that contains our genetic information. Dynamic 3D changes in chromatin are essential for proper embryonic development for example and have been recently implicated in cancer.This proposal will investigate for the first time how chromatin state is affected by nerve injury and how this affects regenerative gene expression in models of nerve and spinal injury in mice. We will not only try to identify important mechanisms but we will also attempt to reshape chromatin structure to promote nerve regeneration.Our studies will use sciatic and spinal nerve injury models in the mouse combined with state of the molecular techniques and bioinformatics analysis that will allow to clarify how gene expression and chromatin structure change after injuryIn summary, our studies will provide a novel understanding of chromatin-dependent regulation of nerve regeneration and will also propose novel avenues to foster repair after nerve and spinal injury.