REST (RE1 silencing transcription factor) is a DNA-binding transcription repressor that functions as a master negative regulator of neuronal gene expression. As a sequence-specific repressor, REST binds to neuron-restrictive silencer elements (NRSE) in target gene promoters to suppress transcription by RNA polymerase II 1. The gene encodes multiple isoforms with distinct functional properties; isoform 1 exhibits full repressor activity, while isoform 3 can be generated through SRRM4-dependent alternative splicing 1. REST plays critical roles in nervous system development by preventing premature neuronal differentiation and maintaining the non-neuronal cell fate. Notably, post-transcriptional inactivation of REST through alternative splicing into isoform 3 is essential for neuronal gene derepression in mechanosensory hair cells, which is required for normal hearing function. Mutations in REST are associated with autosomal dominant deafness (DFNA27), gingival fibromatosis type 5, and Wilms tumor 6, highlighting its importance in organ development and cellular differentiation. The gene's expression is responsive to various cellular signals including electrical stimulation and glucocorticoid exposure, enabling REST to integrate developmental and environmental cues in regulating neuronal cell fate determination.