REST: An epigenetic regulator of neuronal stress responses in the young and ageing brain

The transcriptional repressor REST (Repressor Element-1 Silencing Transcription factor) is a key modulator of the neuronal epigenome and targets genes involved in neuronal differentiation, axonal growth, vesicular transport, ion channel conductance and synaptic plasticity. Whilst its gene expression-modifying properties have been examined extensively in neuronal development, REST's response towards stress-induced neuronal insults has only recently been explored. Overall, REST appears to be an ideal candidate to fine-tune neuronal gene expression following different forms of cellular, neuropathological, psychological and physical stressors. Upregulation of REST is reportedly protective against premature neural stem cell depletion, neuronal hyperexcitability, oxidative stress, neuroendocrine system dysfunction and neuropathology. In contrast, neuronal REST activation has also been linked to neuronal dysfunction and neurodegeneration. Here, we highlight key findings and discrepancies surrounding our current understanding of REST's function in neuronal adaptation to stress and explore its potential role in neuronal stress resilience in the young and ageing brain.