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Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration

Cheng, Y;Yin, Y;Zhang, A;Bernstein, A;Kawaguchi, R;Gao, K;Potter, K;Gilbert, H;Ao, Y;Ou, J;Fricano-Kugler, C;Goldberg, J;Woolf, C;Sofroniew, M;Benowitz, L;Geschwind, D;

The inability of neurons to regenerate long axons within the CNS is a major impediment to improving outcome after spinal cord injury, stroke, and other CNS insults. Recent advances have uncovered an intrinsic program that involves coordinate regulation by multiple transcription factors that can be manipulated to enhance growth in the peripheral nervous system. Here, we used a system-genomics approach to characterize regulatory relationships of regeneration-associated transcription factors, identifying RE1-Silencing Transcription Factor (REST; Neuron-Restrictive Silencer Factor, NRSF) as a predicted upstream suppressor of a pro-regenerative gene program associated with axon regeneration in the CNS. We validate our predictions using multiple paradigms, showing that mature mice bearing cell type-specific deletions of REST or expressing dominant-negative mutant REST showed improved regeneration of the corticospinal tract and optic nerve, accompanied by upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells, respectively. These analyses identify a novel role for REST as an upstream suppressor of the intrinsic regenerative program in the CNS and demonstrate the power of a systems biology approach involving integrative genomics and bio-informatics to predict key regulators of CNS repair.