Epigenetic Regulation of Axon Outgrowth and Regeneration in CNS Injury: The First Steps Forward

Abstract

Inadequate axonal sprouting and lack of regeneration limit functional recovery following neurologic injury, such as stroke, brain, and traumatic spinal cord injury. Recently, the enhancement of the neuronal regenerative program has led to promising improvements in axonal sprouting and regeneration in animal models of axonal injury. However, precise knowledge of the essential molecular determinants of this regenerative program remains elusive, thus limiting the choice of fully effective therapeutic strategies. Given that molecular regulation of axonal outgrowth and regeneration requires carefully orchestrated waves of gene expression, both temporally and spatially, epigenetic changes may be an ideal regulatory mechanism to address this unique need. While recent evidence suggests that epigenetic modifications could contribute to the regulation of axonal outgrowth and regeneration following axonal injury in models of stroke, and spinal cord and optic nerve injury, a number of unanswered questions remain. Such questions require systematic investigation of the epigenetic landscape between regenerative and non-regenerative conditions for the potential translation of this knowledge into regenerative strategies in human spinal and brain injury, as well as stroke.

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

“…Epigenetic Mechanisms of Axon Regeneration-As epigenetic regulation of gene expression becomes more fully understood, the prospect that the epigenetic state of the neuron might significantly influence its intrinsic growth capacity becomes more compelling (168,169). In the last few years, experimental manipulation of chromatin dynamics in injury models has provided valuable insight into epigenetic influence on axon regeneration.…”

The Epigenetics of Stroke Recovery and Rehabilitation: From Polycomb to Histone Deacetylases

“…Acetylation of histone tails interdicts electrostatic interactions between histone proteins and DNA, and thus favors a more transcriptionally competent state [46,47]. As transcription appears to be required for neurite outgrowth, a reasonable model is that small molecules that bias histones toward an acetylated state [histone acetyltransferase activators (see article by Boutillier et al in this issue [48]) or HDAC inhibitors (see articles by Di Giovanni et al [49], Wagner et al [50], and Roskams et al [51] in this issue)] should enhance neurite outgrowth and stroke recovery. HDAC inhibitors are believed to bias gene expression toward the growth program via effects on nuclear and axonal HDACs.…”

Mechanisms of Axonal Damage and Repair after Central Nervous System Injury

“…DNA chromatin modifications alter gene expression, a process known as epigenetic regulation. Recent studies have demonstrated that epigenetic regulation could be closely related to development, plasticity of neurogenesis, and axonal outgrowth and regeneration (reviews by Lindner et al and Hirabayashi et al [33, 34]). Roughly speaking, epigenetic regulation can be categorized into DNA methylation and histone modification.…”