Transcriptional repressor which binds neuron-restrictive silencer element (NRSE) and represses neuronal gene transcription in non-neuronal cells (By similarity). Restricts the expression of neuronal genes by associating with two distinct corepressors, SIN3A and RCOR1, which in turn recruit histone deacetylase to the promoters of REST-regulated genes (By similarity). Mediates repression by recruiting the BHC complex at RE1/NRSE sites which acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier (PubMed:9454838). Transcriptional repression by REST-CDYL via the recruitment of histone methyltransferase EHMT2 may be important in transformation suppression (By similarity). Represses the expression of SRRM4 in non-neural cells to prevent the activation of neural-specific splicing events and to prevent production of REST isoform 6 (By similarity). Repressor activity may be inhibited by forming heterodimers with isoform 6, thereby preventing binding to NRSE or binding to corepressors and leading to derepression of target genes (By similarity). Also maintains repression of neuronal genes in neural stem cells, and allows transcription and differentiation into neurons by dissociation from RE1/NRSE sites of target genes (By similarity). Thereby is involved in maintaining the quiescent state of adult hippocampal neural stem cells and preventing premature differentiation into mature neurons (By similarity). Plays a role in the developmental switch in synaptic NMDA receptor composition during postnatal development, by repressing GRIN2B expression and thereby altering NMDA receptor properties from containing primarily GRIN2B to primarily GRIN2A subunits (PubMed:22960932). Acts as a regulator of osteoblast differentiation (By similarity). Key repressor of gene expression in hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE site on their promoter regions (By similarity). May also function in stress resistance in the brain during aging; possibly by regulating expression of genes involved in cell death and in the stress response (By similarity). Repressor of gene expression in the hippocampus after ischemia by directly binding to RE1/NRSE sites and recruiting SIN3A and RCOR1 to promoters of target genes, thereby promoting changes in chromatin modifications and ischemia-induced cell death (PubMed:22371606, PubMed:12657670). After ischemia, might play a role in repression of miR-132 expression in hippocampal neurons, thereby leading to neuronal cell death (PubMed:25108103). Binds to the 3' region of the neuron-restrictive silencer element (NRSE), with lower affinity than full-length REST isoform 1 (By similarity). Exhibits weaker repressor activity compared to isoform 1 (By similarity). May negatively regulate the repressor activity of isoform 1 by binding to isoform 1, thereby preventing its binding to NRSE and leading to derepression of target genes (By similarity). However, in another study, does not appear to be implicated in repressor activity of a NRSE motif-containing reporter construct nor in inhibitory activity on the isoform 1 transcriptional repressor activity (By similarity). Post-transcriptional inactivation of REST by SRRM4-dependent alternative splicing into isoform 6 is required in mechanosensory hair cells in the inner ear for derepression of neuronal genes and hearing (By similarity). Isoform 1 and isoform 6 form heterodimers (By similarity). Isoform 6: Forms homodimers and homooligomers; binds to the neuron-restrictive silencer element (NRSE) as monomer (By similarity). Interacts with SIN3A, SIN3B and RCOR1 (By similarity). Interacts with CDYL (By similarity). Interacts with EHMT1 and EHMT2 only in the presence of CDYL (By similarity). Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2 (By similarity). Interacts (via zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the interaction inhibits REST repressor activity (By similarity). Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (By similarity). Interacts with FBXW11 and BTRC (By similarity). Interacts with USP7 (By similarity). Colocalizes with ZFP90 in the nucleus (By similarity). In response to hypoxia, there is a more pronounced increase in levels in the nucleus as compared to the cytoplasm (By similarity). In aging neurons, increased levels in the nucleus as compared to the cytoplasm (By similarity). Expressed in the hippocampus including the granule cell layer of the dentate gyrus, the pyramidal cell layers of CA1 and CA3, the apical and basilar dendrite layers of the stratum radiatum and stratum oriens of CA1, the stratum lucidum and stratum oriens of CA3 and in astroglia (at protein level) (PubMed:22960932, PubMed:22371606, PubMed:12657670). Expressed in the brain, with the highest levels in the neurons of hippocampus, pons/medulla and midbrain (PubMed:9454838, PubMed:25108103). Levels decrease during embryonic brain development (PubMed:9454838). Expressed during postnatal days P3 to P60, with an increase in expression at postnatal day P14-P15 (PubMed:22960932). Increased abundance in the nucleus at P14-P15 relative to P9 (PubMed:22960932). Up-regulated by kainic acid (PubMed:9454838). Up-regulated in the pyramidal cell layer of CA1 in the hippocampus by global ischemia (PubMed:25108103, PubMed:22371606, PubMed:12657670). Down-regulated in the hippocampus by maternal deprivation (PubMed:22960932). The C2H2-type zinc finger 5 is required for nuclear localization. O-glycosylated. Phosphorylated; phosphorylation is required for ubiquitination. Ubiquitinated; ubiquitination is mediated by BTRC and leads to proteasomal degradation in G2 phase (By similarity). Ubiquitination increases during neuronal differentiation (By similarity). Deubiquitinated by USP7; leading to its stabilization and promoting the maintenance of neural progenitor cells (By similarity). Produced by SRRM4-dependent alternative splicing in neurons and inner ear hair cells (By similarity). Lacks the four C-terminal zinc fingers and the RCOR1 corepressor interaction site found in full length REST isoform 1, which are required for full DNA-binding and repressive activity (By similarity). Isoform 6: Controversial data exists concerning the repressor activity of isoform 6. In human, a study showed that human isoform 3 exhibits weak repressor activity of a NRSE motif-containing reporter construct (By similarity). Another report, however, does not observe any isoform 3 repressor activity of a NRSE motif-containing reporter construct (By similarity). Isoform 6: Controversial data also exists regarding the function of isoform 6 on the negative regulation of isoform 1. In mouse, it was shown that isoform 2 negatively regulates the repressor activity of isoform 1 by binding to isoform 1, thereby preventing its binding to NRSE and leading to derepression of target genes (By similarity). Another study in human, however, did not observe any inhibitory activity of human isoform 3 on the isoform 1 transcriptional repressor activity (By similarity).