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

Yuyan Cheng, Yuqin Yin, Alice Zhang, Alexander M. Bernstein, Riki Kawaguchi, Kun Gao, Kyra Potter, Hui-Ya Gilbert, Yan Ao, Jing Ou, Catherine J. Fricano-Kugler, Jeffrey L. Goldberg, Zhigang He, Clifford J. Woolf, Michael V. Sofroniew, Larry I. Benowitz () and Daniel H. Geschwind ()
Additional contact information
Yuyan Cheng: University of California, Los Angeles
Yuqin Yin: Boston Children’s Hospital
Alice Zhang: University of California, Los Angeles
Alexander M. Bernstein: University of California, Los Angeles
Riki Kawaguchi: University of California, Los Angeles
Kun Gao: University of California, Los Angeles
Kyra Potter: University of California, Los Angeles
Hui-Ya Gilbert: Boston Children’s Hospital
Yan Ao: University of California, Los Angeles
Jing Ou: University of California, Los Angeles
Catherine J. Fricano-Kugler: University of California, Los Angeles
Jeffrey L. Goldberg: Stanford University
Zhigang He: Boston Children’s Hospital
Clifford J. Woolf: Boston Children’s Hospital
Michael V. Sofroniew: University of California, Los Angeles
Larry I. Benowitz: Boston Children’s Hospital
Daniel H. Geschwind: University of California, Los Angeles

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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 use a systems 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 show improved regeneration of the corticospinal tract and optic nerve after spinal cord injury and optic nerve crush, which is accompanied by upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells, respectively. These analyses identify a role for REST as an upstream suppressor of the intrinsic regenerative program in the CNS and demonstrate the utility of a systems biology approach involving integrative genomics and bio-informatics to prioritize hypotheses relevant to CNS repair.

Date: 2022
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DOI: 10.1038/s41467-022-31960-7

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