REST in the Central Nervous System: Context-Dependent Regulation of Neuronal Homeostasis and Disease

The RE1-silencing transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF), is a zinc-finger domain-containing transcriptional regulator involved in coordinating gene expression programmes in the nervous system. Initially characterized as a repressor of neuronal genes in nonneuronal cells, REST also exerts context-dependent functions during neurodevelopment, neuronal maturation, homeostasis and brain ageing. Its activity involves the recruitment of multiple regulatory complexes, including Sin3A/HDACs and CoREST/LSD1, as well as interactions with mechanisms associated with DNA methylation and hydroxymethylation. REST also integrates regulatory networks involving noncoding RNAs. MicroRNAs such as miR-9, miR-124 and miR-132 participate in networks that interact with REST, contributing to the regulation of neuronal differentiation, maturation and function, whereas interactions with long noncoding RNAs remain less well characterized. Alterations in REST expression, subcellular localization or activity have been associated with various neurological and neurodegenerative conditions. In specific neuronal populations during ageing, nuclear REST has been associated with the regulation of genes involved in stress responses and neuronal resilience, whereas alterations in REST activity have been observed in diseases such as Alzheimer's and Huntington's disease. In addition, mechanistic evidence indicates that cellular metabolic state, particularly alterations in glycolysis and the NADH/NAD⁺ ratio, may influence REST-regulated pathways. In contrast, associations between REST and factors such as physical exercise and creatine availability remain predominantly indirect or hypothetical. In this review, we synthesize the evidence regarding the transcriptional and epigenetic regulatory mechanisms associated with REST, its interactions with noncoding RNA networks and its functions during neuronal development, homeostasis and ageing. We also discuss the interfaces between REST, metabolism and environmental factors, highlighting differences in the strength of the available evidence, current limitations and mechanistic gaps that warrant further investigation.