Transcriptional repressor which binds neuron-restrictive silencer element (NRSE) and represses neuronal gene transcription in non-neuronal cells (PubMed:29961578, PubMed:9771705). 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 (By similarity). 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 2 (PubMed:21884984). Repressor activity may be inhibited by forming heterodimers with isoform 2, thereby preventing binding to NRSE or binding to corepressors and leading to derepression of target genes (PubMed:10490617, PubMed:11039732). 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 (PubMed:15907476). Thereby is involved in maintaining the quiescent state of adult neural stem cells and preventing premature differentiation into mature neurons (PubMed:27819263). 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 (By similarity). Acts as a regulator of osteoblast differentiation (PubMed:25727884). 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 (PubMed:24670762). 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 (By similarity). After ischemia, might play a role in repression of miR-132 expression in hippocampal neurons, thereby leading to neuronal cell death (By similarity). Binds to the 3' region of the neuron-restrictive silencer element (NRSE), with lower affinity than isoform 1 (PubMed:11039732). 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 (PubMed:11039732, PubMed:10490617). 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 2 is required in mechanosensory hair cells in the inner ear for derepression of neuronal genes, maintenance of hair cells and hearing (PubMed:29961578). Isoform 1 and isoform 2 form heterodimers (PubMed:10490617). Isoform 2: Forms homodimers and homooligomers; binds to the neuron-restrictive silencer element (NRSE) as monomer (PubMed:11039732). 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 (PubMed:21284946). 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 (PubMed:21284946). 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 quiescent neuronal progenitor (QNP) cells, transient-amplifying progenitor (TAP) cells, neuroblasts and mature neurons (at protein level) (PubMed:27819263). Expressed in embryonic stem cells (at protein level) (PubMed:15907476). Expressed in many non-neuronal tissues including the heart and liver (PubMed:7871435). Abundantly expressed in osteoblastic lineage cells (PubMed:25727884). Expressed in the spleen, kidney, blood cells, cortex, neocortex and in the utricle, saccule and organ of Corti of the inner ear (PubMed:29961578). Isoform 2: Expressed in the cortex, neocortex and in the utricle, saccule and organ of Corti of the inner ear (PubMed:29961578). Ubiquitously expressed in 8.5 dpc and 9.5 dpc embryos (PubMed:9771705). During embryogenesis, expressed at high levels in non-neuronal and differentiated peripheral nervous tissues, but is not expressed in differentiating neurons in the CNS (PubMed:7697725, PubMed:7871435). Expressed in the neocortex at embryonic stage 14.5 dpc and 16 dpc and in the utricle at 15.5 dpc (PubMed:29961578). Isoform 2: Expressed in the neocortex at embryonic stage 14.5 dpc and 16 dpc and in the utricle and saccule at 16 dpc (PubMed:29961578). Down-regulated in differentiating neurons and mature neurons. 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). Embryonic lethality by embryonic day 11.5 dpc (PubMed:9771705). At 9.25 dpc, disorganization of the head mesenchyme in the midbrain region with separation of myotomal cells from the dermomyotome and widespread apoptotic cell death (PubMed:9771705). Forebrain malformation and widening of the mesencephalic flexure at 9.5 dpc and 10.5 dpc, and growth retardation by 10.5 dpc (PubMed:9771705). Conditional knockout in the nervous system results in a progressive age-related neurodegenerative phenotype (PubMed:24670762). At the age of 1 month, no change of neuronal numbers in the cortex and hippocampus, but at the age of 8 months, neuronal degeneration and apoptosis, accompanied by significant neuronal loss in the cerebral cortex and hippocampus, and pronounced gliosis (PubMed:24670762). In primary 16 dpc cortical neurons, increased degeneration and cell death upon oxidative stress or exposure to oligomeric amyloid-beta 42 (PubMed:24670762). Conditional knockout in QNP cells leads to a higher number of proliferating QNP cells, an increased transition to TAP cells and increased differentiation into mature neurons (PubMed:27819263). Conditional knockdout in proliferating cells leads to a decreased number of proliferating TAP cells and an increase in immature and mature neurons (PubMed:27819263). Produced by SRRM4-dependent alternative splicing in neurons and inner ear hair cells (PubMed:11039732, PubMed:29961578). 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 (PubMed:11039732, PubMed:29961578). Controversial data exists concerning the repressor activity of isoform 2. A study in human 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 transcriptional repressor activity of a NRSE motif-containing reporter construct (By similarity). Controversial data also exists regarding the function of isoform 2 on the negative regulation of full-length REST. 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 (PubMed:10490617, PubMed:11039732). Another study in human, however, did not observe any inhibitory activity of human isoform 3 on the isoform 1 repressor activity (By similarity). Contaminating sequence. Potential poly-A sequence.