Characterizing chromatin changes and transcriptional regulatory mechanisms driving growth-related transcription
Funded in: 2020, 2021, 2022
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Problem: Inability of mature neurons to regenerate lengthy axons within the CNS
Target: Insight into the transcriptional and epigenetic mechanisms that change the intrinsic growth state of CNS neurons
Goal: Drive regeneration-associated transcription for neural repair
The inability of mature neurons to regenerate lengthy axons within the CNS is a substantial impediment for treatments directed at improving spinal cord injury (SCI). Unlike their CNS counterparts, peripheral neurons spontaneously display potent growth in response to axonal injury. This distinction between CNS and PNS regenerative capacity is due to both intrinsic and extrinsic factors, the latter including growth-limiting molecules such as CSPG and myelin present in CNS injured tissue environment. However, even in the context of inhibitory extrinsic factors, modulating intrinsic factors can overcome extrinsic inhibition to induce appreciable axon growth, suggesting the essential role of cell-intrinsic mechanisms underlying axon regeneration. Enhancing neurons’ intrinsic growth state involves activation of key regeneration-associated genes (RAGs) that the scientists recently found to act as a coordinated network controlled by a set of transcription factors (TFs) to promote growth. The researchers reasoned that coordinated expression of the RAG network would enhance intrinsic capacity of adult CNS neurons and improve regenerative success. Gene expression is modulated by TFs, and the epigenetic mechanisms that change the local chromatin environment to be permissive or non-permissive for transcription. The scientists propose to identify: 1) key TFs that act on the upstream of the RAG network to drive regeneration in response to SCI; and 2) the epigenetic factors to remodel chromatin so as to be permissive for initiating RAG transcription in CNS neurons. This study will provide insight into the transcriptional and epigenetic mechanisms that change the intrinsic growth state of CNS neurons so as to identify novel therapeutic targets to advance regeneration after SCI. Since epigenetic processes that regulate chromatin structure are the targets of multiple drugs used in humans, identifying chromatin remodelers to drive regeneration-associated transcription for neural repair has high translational potential.