Affinage

REST

RE1-silencing transcription factor · UniProt Q13127

Length
1097 aa
Mass
121.9 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

REST/NRSF is a zinc-finger transcriptional repressor that imposes a non-neuronal gene expression program by binding RE1/NRSE elements in the promoters of neuronal genes and is required in vivo to keep these genes silent in non-neural tissues and undifferentiated neural progenitors, with its loss causing derepression of neuronal targets and embryonic lethality (PMID:9771705, PMID:15907476). Variation in the RE1 motif sequence encodes a hierarchy of binding affinities, so that canonical sites control genes common to all cell types while atypical weak sites control tissue-specific targets, coupling REST occupancy to chromatin configuration and target expression (PMID:19401398). REST silences targets by recruiting corepressor machinery: CDYL physically bridges REST to the histone methyltransferase G9a to deposit repressive H3K9 methylation (PMID:19061646, PMID:28483947), and the purified C-terminal REST complex is intrinsically competent for histone deacetylation and demethylation at RE1/NRSE sites (PMID:28218430). During neurogenesis REST is degraded to poise neuronal chromatin and then dissociates from RE1 to permit neuronal gene activation, a switch further tuned by the truncated isoform REST4, which competitively antagonizes full-length REST repression (PMID:15907476, PMID:11779185). REST function is gated by regulated nuclear import—dependent on the prenylated, PKA-phosphorylated LIM-domain receptor RILP and on a nuclear localization signal around zinc finger domain 5—and by cytoplasmic sequestration; wild-type huntingtin holds REST in the cytoplasm, and its loss in Huntington's disease drives aberrant nuclear REST and silencing of neuronal genes including BDNF (PMID:14645515, PMID:16417580, PMID:16442230, PMID:12881722). Upstream, REST expression is induced by canonical Wnt/β-catenin signaling (PMID:14575694) and by stress stimuli including hypoxia and IL-1β (PMID:27531581, PMID:33589593). Beyond neurons, REST governs adult neural stem cell quiescence through ribosome biogenesis and cell cycle targets (PMID:27819263), homeostatic synaptic plasticity via Npas4/BDNF/TrkB programs (PMID:34855580), cardiomyocyte proliferation through repression of p21 (PMID:29215012), pancreatic endocrine differentiation (PMID:34385258), and neuronal proteostasis and stress resistance during aging, where its loss from the nucleus and accumulation in autophagosomes with misfolded proteins contributes to neurodegeneration (PMID:24670762, PMID:34520100). Truncating mutations in the final exon of REST cause hereditary gingival fibromatosis in humans (PMID:28686854).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1998 High

    Established that REST is genuinely required in vivo to silence neuronal genes outside the nervous system, moving it from a candidate repressor to an essential developmental regulator.

    Evidence Targeted Rest knockout in mice and dominant-negative NRSF in chicken embryos with in situ hybridization for neuronal targets

    PMID:9771705

    Open questions at the time
    • Did not resolve the corepressor machinery executing repression
    • Embryonic lethality limited analysis of tissue-specific roles
  2. 2002 Medium

    Identified that the neuron-specific truncated isoform REST4 antagonizes full-length REST at RE1/NRSE sites, providing a built-in mechanism to derepress neuronal genes such as BDNF.

    Evidence Reporter co-expression assays of REST4 and full-length REST in rat cortical neurons

    PMID:11779185

    Open questions at the time
    • Reporter-based; endogenous stoichiometry of isoforms not measured
    • Mechanism of antagonism (DNA competition vs corepressor sequestration) not resolved
  3. 2003 High

    Showed REST localization is actively controlled by cytoplasmic sequestration and identified RILP as a dedicated nuclear targeting receptor, framing nuclear access—not just DNA binding—as a regulatory layer.

    Evidence Co-IP of huntingtin with REST and NRSE reporter assays across HD models; yeast two-hybrid identifying RILP

    PMID:12881722 PMID:14645515

    Open questions at the time
    • Mechanism by which huntingtin retains REST in cytoplasm not fully defined
    • RILP identification was Y2H-based at this stage
  4. 2003 High

    Extended REST's repressive role beyond neurons to the cardiovascular system and placed REST expression under Wnt/β-catenin/TCF control, defining an upstream input.

    Evidence Dominant-negative NRSF transgenic heart with electrophysiology; in ovo chick reporter assays with TCF site mutagenesis

    PMID:14575694 PMID:14633990

    Open questions at the time
    • Direct cardiac target gene occupancy by REST not established here
    • Wnt regulation shown in chick; conservation in mammals not tested
  5. 2005 High

    Resolved the dynamic logic of REST during neurogenesis—degradation to poise chromatin in progenitors then corepressor dissociation at neuronal maturation—explaining how a repressor permits staged gene activation.

    Evidence Expression profiling and chromatin/corepressor association analysis across neuronal differentiation

    PMID:15907476

    Open questions at the time
    • Degradation machinery targeting REST not identified here
    • Quantitative thresholds governing the poised state undefined
  6. 2006 High

    Defined the biochemical requirements for REST nuclear import, showing RILP prenylation, NLS integrity and PKA phosphorylation are needed and that a ZFD-5-proximal signal—not the previously proposed NLS—drives REST nuclear localization.

    Evidence Prenylation labeling, NLS/phospho-site mutagenesis, co-localization and reporter assays; systematic localization-signal mutagenesis in HeLa/COS/PC12

    PMID:16417580 PMID:16442230

    Open questions at the time
    • Importin pathway downstream of RILP not mapped
    • How signaling regulates RILP modifications in neurons not defined
  7. 2008 High

    Defined a specific corepressor module—CDYL bridging REST to G9a—and linked REST-mediated repression to suppression of oncogenic transformation via the TrkC oncogene.

    Evidence Reciprocal Co-IP, RNAi knockdown, ChIP, and transformation assays in human cells

    PMID:19061646

    Open questions at the time
    • Genome-wide scope of CDYL-G9a use versus CoREST not defined
    • Structural basis of CDYL bridging not determined
  8. 2009 High

    Mapped how RE1 sequence variation encodes graded REST binding affinity, explaining how one repressor produces both ubiquitous and tissue-specific repression outcomes.

    Evidence Genome-wide ChIP-seq with comparative analysis of RE1 motif sequences and target chromatin/expression

    PMID:19401398

    Open questions at the time
    • Did not establish how weak-site occupancy is stabilized in specific tissues
    • Cofactor contributions to affinity not dissected
  9. 2012 Medium

    Placed REST in a regulatory hierarchy by identifying ZNF335 as an essential upstream activator of REST controlling neural progenitor self-renewal.

    Evidence Complex purification/MS, conditional Znf335 knockout, RNAi, and ChIP at the REST locus

    PMID:23178126

    Open questions at the time
    • Direct ZNF335 occupancy mechanism at REST promoter not fully resolved
    • Generalizability beyond neural progenitors untested
  10. 2014 High

    Established REST as a neuroprotective factor in aging, repressing cell-death/AD-pathology genes and inducing stress responses, with nuclear loss and autophagosomal sequestration linking REST dysfunction to neurodegeneration.

    Evidence ChIP-seq, conditional REST knockout mouse, oxidative/Aβ stress protection assays, and immunofluorescence in AD/FTD/DLB tissue

    PMID:24670762

    Open questions at the time
    • Trigger for REST mislocalization into autophagosomes not mechanistically defined
    • Causality of REST loss versus consequence in human disease not fully resolved
  11. 2015 Medium

    Identified TSPYL2 as a REST complex component coupling REST to TGFβ signaling and cell cycle arrest, broadening REST's tumor-suppressive control of TrkC.

    Evidence Co-IP, RNAi knockdown, TGFβ signaling and transformation assays in human mammary epithelial cells

    PMID:25613376

    Open questions at the time
    • Stoichiometry and architecture of the TSPYL2/REST complex unknown
    • Single cell-type context
  12. 2016 High

    Defined a non-neuronal/quiescence role: REST maintains adult hippocampal neural stem cell dormancy by directly repressing ribosome biogenesis and cell cycle genes, with single-target gain-of-function sufficient to activate progenitors.

    Evidence Conditional REST knockout, ChIP-seq, RNA-seq, and individual target overexpression

    PMID:27819263

    Open questions at the time
    • Signals that release REST repression during physiological activation not defined
    • Corepressor usage at quiescence targets not specified
  13. 2016 Medium

    Showed REST nuclear localization and repressive activity are stress-inducible, accounting for a fraction of hypoxia-repressed genes through direct promoter binding.

    Evidence RNA-seq, ChIP, and nuclear fractionation/immunofluorescence under hypoxia in HEK293

    PMID:27531581

    Open questions at the time
    • Upstream signal driving hypoxia-induced REST nuclear accumulation not defined
    • Limited to one cell line
  14. 2016 Medium

    Provided a global REST interactome and a specific functional partnership with TRIM28 in restraining neuronal differentiation genes such as CTNND2.

    Evidence Affinity purification-mass spectrometry, Co-IP, siRNA knockdown, and neurite outgrowth assays

    PMID:27976729

    Open questions at the time
    • Most of the 204 interactors not functionally validated
    • Direct versus indirect membership in REST complexes not distinguished
  15. 2017 High

    Reconstituted the human C-terminal REST repressor complex in vitro and demonstrated intrinsic histone deacetylase/demethylase activity at RE1 sites, providing direct biochemical proof of REST's enzymatic repressive machinery and a druggable target.

    Evidence Baculovirus multiprotein expression/purification, in vitro deacetylation/demethylation and DNA-binding assays, small-molecule inhibitor studies

    PMID:28218430

    Open questions at the time
    • Subunit composition of the reconstituted complex not enumerated in narrative terms
    • In-cell relevance of inhibitor specificity not fully established
  16. 2017 High

    Defined a REST-p21 axis controlling cardiomyocyte proliferation, shown by genetic epistasis where p21 deletion rescues the cell cycle defect of Rest loss.

    Evidence Conditional REST knockout, ChIP at p21, overexpression, p21 double-knockout rescue, and cardiac regeneration assays

    PMID:29215012

    Open questions at the time
    • Other proliferative targets beyond p21 not delineated
    • Direct corepressor at the p21 locus not identified
  17. 2017 Medium

    Demonstrated REST recruits G9a to deposit H3K9 methylation at a specific oncogenic target (USP37) in medulloblastoma, connecting REST dosage to enzymatic chromatin modification and tumor biology.

    Evidence ChIP for H3K9 methylation, genetic/pharmacological G9a inhibition, isogenic REST-level cell lines, and orthotopic mouse model

    PMID:28483947

    Open questions at the time
    • Generality of G9a recruitment across REST targets not assessed
    • Single tumor context
  18. 2017 Medium

    Showed REST/NRSF mediates an environmentally driven, durable epigenetic repression of the stress gene Crh, linking neuronal activity to lasting chromatin silencing in vivo.

    Evidence ChIP-seq for NRSF binding, epigenetic mark analysis, in vitro neurotransmission manipulation, and behavioral testing in mice

    PMID:28070121

    Open questions at the time
    • Mechanism sustaining repression after NRSF dissociation not defined
    • Causal link between Crh repression and behavior partial
  19. 2017 Medium

    Established a human Mendelian disease link, showing truncating mutations in the final REST exon cause hereditary gingival fibromatosis and implicating the C-terminal domain.

    Evidence Whole-exome sequencing of HGF families with Sanger confirmation

    PMID:28686854

    Open questions at the time
    • No cellular functional mechanism for the mutations reported
    • Tissue-specific basis of the fibromatosis phenotype unexplained
  20. 2020 Medium

    Defined an upstream signaling route—mGluR5 acting through the N-cadherin/β-catenin complex in a Src-dependent manner—that controls REST expression and is therapeutically tractable in Huntington's disease models.

    Evidence Primary corticostriatal neuron culture, pharmacological modulation, Co-IP of N-cadherin/β-catenin, Src inhibition, and HD mouse validation

    PMID:32859226

    Open questions at the time
    • Direct transcriptional effectors at the REST promoter not mapped
    • Single lab
  21. 2021 High

    Established REST as an effector of homeostatic synaptic plasticity, driving target-specific inhibitory synapse scaling via Npas4/BDNF/TrkB programs.

    Evidence Electrophysiology (mIPSC/eIPSC), TrkB inhibition, REST knockdown/conditional knockout, and synapse density immunocytochemistry in mouse hippocampal neurons

    PMID:34855580

    Open questions at the time
    • Direct REST targets executing inhibitory scaling not enumerated
    • Mechanism of target-specificity not resolved
  22. 2021 High

    Linked inflammatory signaling to synaptic depression, showing IL-1β induces REST via Wnt/β-catenin to drive excitatory synaptic downscaling, with REST deletion abolishing the effect.

    Evidence Cytokine/pharmacological treatments, REST conditional knockout neurons, mEPSC recording, calcium imaging, and synapse density assays

    PMID:33589593

    Open questions at the time
    • REST target genes mediating excitatory downscaling not identified
    • In vivo relevance to inflammatory neuropathology untested here
  23. 2021 Medium

    Identified a cell-autonomous mechanism of REST neuroprotection, showing REST maintains autophagic flux and proteostasis to prevent neuronal senescence, with autophagy restoration reversing REST-deficiency phenotypes.

    Evidence REST knockout/knockdown in primary mouse neurons, autophagy flux and senescence markers, and rescue by autophagy restoration

    PMID:34520100

    Open questions at the time
    • Direct REST targets controlling autophagy not identified
    • Relationship to autophagosomal REST sequestration in disease unresolved
  24. 2021 High

    Demonstrated REST is a major brake on pancreatic endocrine differentiation across species, extending its repressive role to non-neural organogenesis.

    Evidence Conditional REST knockout, zebrafish inhibition, human duct organoids, and ChIP-seq in embryonic pancreas

    PMID:34385258

    Open questions at the time
    • Specific endocrine-fate genes repressed not fully delineated in narrative
    • Corepressor complexes used in pancreas not identified
  25. 2024 Medium

    Defined a REST→LRSAM1→SLC40A1 axis controlling iron handling and ferroptosis, providing a route by which inhibiting REST repression sensitizes drug-resistant glioma stem cells to cell death.

    Evidence Co-IP, ubiquitination and protein stability assays, ChIP, reporter assays, and ferroptosis markers in TMZ-resistant glioma stem cells

    PMID:39039049

    Open questions at the time
    • Direct REST occupancy at LRSAM1 versus indirect regulation needs further confirmation
    • Single cancer model

Open questions

Synthesis pass · forward-looking unresolved questions
  • The signals and machinery that switch REST between nuclear repression, regulated degradation, and pathological autophagosomal sequestration remain incompletely defined across the diverse tissues REST controls.
  • E3 ligases and degradation pathway targeting nuclear REST not identified in the corpus
  • Rules selecting among CoREST, CDYL-G9a, and TSPYL2 corepressor modules at a given locus unknown
  • Mechanism routing REST into autophagosomes with misfolded proteins in neurodegeneration unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 2
Partners
CDYLG9AHTTMECP2RILPTRIM28TSPYL2
Complex memberships
CDYL-G9a corepressor complexCoREST complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 REST regulates transitions from pluripotent to neural stem/progenitor cell and from progenitor to mature neuron. In the transition to progenitor, REST is degraded to levels sufficient to maintain neuronal gene chromatin in an inactive but poised state. As progenitors differentiate into neurons, REST and its co-repressors dissociate from the RE1 site, triggering activation of neuronal genes. In some neurons, CoREST/MeCP2 repressor complexes remain bound at methylated DNA sites distinct from RE1, further adjusting expression levels. Expression profiling, chromatin analysis, and mechanistic dissection of REST/corepressor complex association/dissociation during neurogenesis Cell High 15907476
2003 Wild-type huntingtin sequesters REST/NRSF in the cytoplasm of neurons, preventing it from entering the nucleus and repressing NRSE-controlled neuronal genes (including BDNF). Mutant huntingtin loses this interaction, resulting in aberrant accumulation of REST/NRSF in the nucleus and loss of NRSE-controlled neuronal gene transcription in Huntington's disease. Co-immunoprecipitation of huntingtin with REST/NRSF; luciferase reporter assays for NRSE activity; expression analysis in HD cells, mice and human brain Nature genetics High 12881722
2014 REST represses genes that promote cell death and Alzheimer's disease pathology, and induces stress response genes, thus protecting neurons from oxidative stress and amyloid-β toxicity. Conditional deletion of REST in mouse brain leads to age-related neurodegeneration. In Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Wnt signaling (cell non-autonomous) is identified as a mechanism that induces REST during normal aging. ChIP-seq and expression analysis; conditional REST knockout mouse model; neuronal protection assays (oxidative stress, Aβ toxicity); immunofluorescence localization of REST to autophagosomes Nature High 24670762
1998 NRSF/REST is required in vivo to repress neuronal gene expression in non-neural tissues and undifferentiated neural progenitors. Targeted mutation of Rest in mice caused derepression of neuron-specific tubulin in non-neural tissues and embryonic lethality. Dominant-negative NRSF in chicken embryos similarly derepressed multiple neuronal target genes in non-neural tissues and CNS neuronal progenitors. Targeted gene knockout in mice; dominant-negative expression in chicken embryos; in situ hybridization for neuronal target genes Nature genetics High 9771705
2008 CDYL physically bridges REST and the histone methyltransferase G9a to form a corepressor complex. RNAi knockdown of REST, CDYL, and G9a (but not CoREST) induced oncogenic transformation of immortalized primary human cells and derepressed the proto-oncogene TrkC. Transgenic expression of TrkC also induced transformation, implicating CDYL-G9a in REST-mediated suppression of cellular transformation via oncogene repression. Co-immunoprecipitation; RNAi knockdown; oncogenic transformation assays; ChIP; overexpression of TrkC Molecular cell High 19061646
2003 NRSF/REST is a transcriptional repressor of multiple fetal cardiac genes, including those for atrial natriuretic peptide, brain natriuretic peptide, and alpha-skeletal actin. Transgenic mice expressing a dominant-negative NRSF in the heart exhibit dilated cardiomyopathy, arrhythmias, and sudden death. NRSF also regulates genes encoding ion channels carrying fetal cardiac currents I(f) and I(Ca,T). Dominant-negative transgenic mouse model; cardiac gene expression analysis; electrophysiological assessment; reporter gene assays The EMBO journal High 14633990
2003 REST/NRSF-interacting LIM domain protein (RILP), a novel protein containing three LIM domains, putative nuclear localization sequences, protein kinase A phosphorylation sites, and a CAAX prenylation motif, was identified as a nuclear translocation receptor for REST/NRSF and REST4. RILP is localized around the nucleus and is involved in determining the nuclear localization of REST/NRSF and REST4. Yeast two-hybrid screen using REST/NRSF N-terminal zinc finger domain as bait; co-localization studies Molecular and cellular biology Medium 14645515
2006 RILP is prenylated at its CAAX motif, and its PKA phosphorylation sites are phosphorylated. Blocking RILP prenylation, mutating its nuclear localization sequences, or mutating PKA phosphorylation sites causes RILP to mislocalize to the cytosol, concurrent with co-localization of REST/NRSF and REST4 in the cytosol. RILP mutants prevent repression of a cholinergic locus reporter gene by trapping REST/NRSF in the cytoplasm, demonstrating that RILP is required for REST/NRSF nuclear targeting and transcriptional repressor function. [3H]-mevalonolactone labeling for prenylation; phosphorylation analysis; NLS mutation and co-localization; reporter gene assays Journal of neurochemistry High 16417580
2006 Nuclear localization of REST/NRSF depends on a nuclear localization signal around zinc finger domain 5 (ZFD-5), not on the previously proposed NLS at residues 512–522. Deletion of ZFD-5, but not deletion/mutation of residues 512–522, causes mislocalization of REST/NRSF to the cytosol. Deletion and point mutation constructs of REST/NRSF; subcellular localization by fluorescence microscopy in HeLa, COS, and PC12 cells Neuroscience letters Medium 16442230
2009 Variations in the DNA sequence of the RE1 motif encode in vivo DNA binding affinity hierarchies for REST: canonical RE1 motifs facilitate strong REST binding and control target genes common to all cell types, while atypical motifs facilitate weak interactions and control tissue-specific targets. REST binding affinity directly correlates with chromatin configuration and expression of target genes. Chromatin immunoprecipitation followed by genome-wide sequencing; comparative genomic analysis of RE1 motif sequences Genome research High 19401398
2003 The canonical Wnt pathway directly controls NRSF/REST expression. The Wnt-activated β-catenin/TCF complex upregulates REST/NRSF through a conserved element in exon 1a of the REST/NRSF gene. In ovo transcriptional assay in chick spinal cord; reporter gene assays with mutated TCF binding sites Biochemical and biophysical research communications Medium 14575694
2017 REST binds and represses the cell cycle inhibitor gene p21, and is required for cardiomyocyte cell cycle progression in mouse cardiac development and regeneration. Rest deletion de-represses p21 and inhibits cardiomyocyte proliferation; REST overexpression represses p21 and increases proliferation. p21 knockout rescues cardiomyocyte cell cycle defects caused by Rest deletion, establishing a REST-p21 regulatory axis. Conditional REST knockout mouse; ChIP for REST binding at p21 locus; REST overexpression in cultured cardiomyocytes; p21 knockout rescue experiment; cardiac regeneration assays Nature communications High 29215012
2016 Nuclear localization of REST is induced by hypoxia, and REST is responsible for repressing approximately 20% of hypoxia-repressed genes in HEK293 cells. REST-dependent gene repression under hypoxia is mediated at least in part by direct binding to target gene promoters. RNA-seq; ChIP assay for REST binding at promoters under hypoxia; nuclear localization by fractionation/immunofluorescence Scientific reports Medium 27531581
2021 IL-1β causes a potent increase in REST transcription and translation in neurons via activation of Wnt signaling and increased nuclear translocation of β-catenin. REST upregulation in this context promotes a delayed and strong synaptic downscaling specific for excitatory synapses, including decreased frequency/amplitude of spontaneous synaptic currents and decreased excitatory synapse density. Conditional deletion of REST completely blocked the effects of IL-1β on synaptic transmission and network excitability. Pharmacological and cytokine treatments; REST conditional knockout neurons; electrophysiological recording of mEPSCs; calcium imaging; immunocytochemistry for synapse density; Western blotting Cell death & disease High 33589593
2021 REST deficiency causes failure of autophagy and loss of proteostasis, increased oxidative stress, and higher rate of cell death in primary mouse neurons, resulting in a cellular senescence phenotype. Re-establishment of autophagy reverses the main hallmarks of REST-deficiency-induced senescence, showing that REST maintains neuronal health by regulating the autophagic flux. REST knockout/knockdown in primary mouse neurons; autophagy flux assays; senescence markers; cell death assays; rescue by autophagy restoration Aging cell Medium 34520100
2017 REST represses USP37 expression in medulloblastoma via recruitment of G9a histone methyltransferase, which promotes H3K9 mono-, di-, and trimethylation at the USP37 promoter. Using isogenic low- and high-REST cells, high REST levels caused REST-dependent elevation in G9a activity and increased H3K9 methylation with corresponding USP37 downregulation. ChIP for H3K9 methylation at USP37 promoter; genetic and pharmacological inhibition of G9a; isogenic cell lines with varying REST levels; in vivo mouse orthotopic model Molecular cancer research Medium 28483947
2015 TSPYL2 is a novel component of the REST protein complex. REST and TSPYL2 together regulate TGFβ signaling, and TGFβ-induced cell cycle arrest requires both REST and TSPYL2. The TSPYL2/REST complex promotes TGFβ signaling by repressing the proto-oncogene TrkC. Knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Co-immunoprecipitation identifying TSPYL2 in REST complex; RNAi knockdown of REST and TSPYL2; TGFβ signaling assays; transformation assays Cell death and differentiation Medium 25613376
2017 Purified human REST/NRSF and its C-terminal repressor complex are functionally active in histone deacetylation and histone demethylation in vitro, and both bind RE1/NRSE sites. Small-molecule drugs 4SC-202 and SP2509 interfere with the C-terminal REST complex and with medulloblastoma cell viability. Baculovirus multiprotein expression and purification; in vitro histone deacetylation and demethylation assays; RE1/NRSE DNA binding assays; small-molecule inhibitor studies in medulloblastoma cells Protein science High 28218430
2002 REST4, a neuron-specific truncated isoform of REST/NRSF, competitively inhibits the silencing activity of full-length REST/NRSF on the BDNF gene promoter I via the NRSE/RE1 site, and enhances basal transcriptional activity. REST4 thus modulates REST/NRSF repression, preventing neuronal genes from being inactivated and permitting gene activation in response to neuronal stimuli. Transient transfection reporter assays in rat cortical neurons; co-expression of REST4 and REST/NRSF; luciferase assays Biochemical and biophysical research communications Medium 11779185
2007 Full-length REST/NRSF or its C-terminal domain can almost completely inhibit glucocorticoid-induced transcription of glutamine synthetase. By contrast, the N-terminal domain (present in splice variant REST4) not only fails to repress the hormonal response but markedly stimulates it, through recruitment of hBrm to the promoter in the presence of glucocorticoid receptor. Domain deletion constructs; reporter gene assays; ChIP for hBrm recruitment The Journal of biological chemistry Medium 17984088
2016 REST regulates gene networks in adult hippocampal neural stem cells to maintain quiescence. Conditional REST knockout results in precocious activation of quiescent neural progenitors (QNPs) and reduced neurogenesis over time. REST directly targets ribosome biogenesis and cell cycle genes in QNPs; overexpression of individual REST target ribosome biogenesis or cell cycle genes is sufficient to induce QNP activation. Conditional REST knockout; ChIP-seq; RNA-seq; overexpression of individual target genes Nature communications High 27819263
2021 REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-specific manner. Hyperactivity-induced REST activation increases miniature and evoked IPSC frequency/amplitude in mouse hippocampal neurons, specifically at inhibitory-onto-excitatory neuron synapses. Perisomatic inhibition upscaling requires sequential activation of Npas4 and BDNF gene programs via TrkB receptor; dendritic inhibition downscaling is REST-dependent but BDNF-independent. Electrophysiology (mIPSC, eIPSC recording); TrkB inhibition; REST knockdown/conditional knockout; immunocytochemistry for synapse density eLife High 34855580
2020 mGluR5 regulates REST/NRSF expression through the N-cadherin/β-catenin complex in a Src kinase-dependent manner. mGluR5 agonist DHPG or negative allosteric modulator CTEP modulates REST/NRSF expression by regulating N-cadherin/β-catenin assembly. In Huntington's disease mouse models, pharmacological inhibition of mGluR5 rescued pathological REST/NRSF signaling. Primary corticostriatal neuron culture; pharmacological modulation; Co-IP of N-cadherin/β-catenin; Src kinase inhibition; HD mouse model validation Molecular brain Medium 32859226
2016 REST interactome analysis identified 204 REST-interacting proteins by affinity purification and mass spectrometry, including TRIM28. REST and TRIM28 co-regulate neuronal differentiation-related genes, including CTNND2, which increases when both REST and TRIM28 are knocked down. Depletion of either REST or TRIM28 increased neurite outgrowth. Affinity purification-mass spectrometry; co-immunoprecipitation; immunocytochemistry; siRNA knockdown; neurite outgrowth assay Scientific reports Medium 27976729
2017 Truncating mutations in the final exon of REST cause hereditary gingival fibromatosis (HGF) in humans, establishing that loss of REST's C-terminal domain leads to this developmental phenotype. Whole-exome sequencing identifying frameshift and nonsense REST mutations in HGF families; Sanger confirmation American journal of human genetics Medium 28686854
2011 REST governs the expression of dense-core vesicle (DCV) gliosecretion in astrocytes. Astrocytes with high REST levels lack DCVs and their markers; transfection of a dominant-negative REST construct induced appearance of DCVs filled with secretogranin 2 and NPY, which underwent Ca2+-dependent exocytosis sensitive to botulinum toxin B. In human temporal cortex, astrocyte REST levels are variable and inversely correlated with DCV expression. Dominant-negative REST transfection in rat astrocyte cultures; TIRF microscopy for exocytosis; botulinum toxin B inhibition; immunohistochemistry in human brain The Journal of cell biology Medium 21536750
2009 DYRK1A binds the SWI/SNF chromatin remodeling complex, which interacts with REST/NRSF. DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes near REST/NRSF binding sites and perturbs Rest/Nrsf levels. Mutation of a REST/NRSF binding site in the L1cam promoter modifies the transcriptional effect of DYRK1A dosage on L1cam. Co-immunoprecipitation of DYRK1A with SWI/SNF; transgenic DS mouse transcriptome analysis; promoter mutation analysis; primary cortical neuron dendritic growth assays Human molecular genetics Medium 19218269
2017 Augmented maternal care represses the stress-responsive gene Crh in hypothalamic neurons through NRSF recruitment to chromatin, followed by sequential repressive epigenetic changes that outlast NRSF binding. Reduced glutamatergic neurotransmission in vitro recapitulated the repressive effects on Crh, and this required NRSF recruitment. ChIP-seq for NRSF binding; epigenetic mark analysis; in vitro hypothalamic neuron manipulation; behavioral tests in mice Molecular psychiatry Medium 28070121
2021 REST is a major negative regulator of endocrine differentiation during pancreas organogenesis. Using a conditional allele enabling profound REST inactivation, REST-null embryonic pancreas showed a marked increase in endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse postnatal ducts and induced β-cell-specific genes in human adult duct-derived organoids. Genomic REST binding sites in the embryonic pancreas were identified as direct repression targets. Conditional REST knockout with different alleles; zebrafish REST inhibition; human organoid culture; ChIP-seq for REST binding in embryonic pancreas Genes & development High 34385258
2024 Erianin inhibits REST's transcriptional repression function (without altering its expression), leading to upregulation of LRSAM1. LRSAM1 in turn ubiquitinates and degrades SLC40A1, an iron export protein that inhibits ferroptosis. This REST→LRSAM1→SLC40A1 axis mediates erianin-induced ferroptosis in TMZ-resistant glioma stem cells. Co-immunoprecipitation; ubiquitination assays; protein stability assessment; ChIP assay; luciferase reporter gene assays; ferroptosis markers (ROS, GSH, MDA, BODIPY) Cell death & disease Medium 39039049
2012 ZNF335/NIF-1 is a component of a vertebrate-specific trithorax H3K4-methylation complex that directly regulates REST/NRSF. ZNF335 is an essential upstream regulator of REST/NRSF in neural progenitor self-renewal and neurogenesis. Protein complex purification and mass spectrometry; conditional Znf335 knockout; RNAi in neural progenitors; ChIP for ZNF335 at REST locus Cell Medium 23178126

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 1579 21677641
2005 REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 772 15907476
2003 Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nature genetics 734 12881722
2014 REST and stress resistance in ageing and Alzheimer's disease. Nature 613 24670762
2021 Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science (New York, N.Y.) 501 33795428
1998 NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nature genetics 405 9771705
2005 The many faces of REST oversee epigenetic programming of neuronal genes. Current opinion in neurobiology 346 16150588
2007 Chromatin crosstalk in development and disease: lessons from REST. Nature reviews. Genetics 320 17572692
1998 Neuronal expression of zinc finger transcription factor REST/NRSF/XBR gene. The Journal of neuroscience : the official journal of the Society for Neuroscience 316 9454838
2004 A cut above the rest: the regulatory function of plant proteases. Planta 259 15517349
2020 The Molecular Anatomy of Mouse Skin during Hair Growth and Rest. Cell stem cell 255 32109378
1997 Rest heart rate and life expectancy. Journal of the American College of Cardiology 216 9316546
2003 NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. The EMBO journal 176 14633990
2001 The rest is silence. RNA (New York, N.Y.) 162 11720281
2000 The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells. Nature medicine 151 10888935
2012 Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation. Cell 133 23178126
2008 DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome. American journal of human genetics 130 18771760
2006 Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Molecular and cellular biology 125 16478988
2008 CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation. Molecular cell 124 19061646
2010 REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions. Cell cycle (Georgetown, Tex.) 119 21088488
1999 Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat. Brain research. Molecular brain research 115 10521596
2009 REST and CoREST modulate neuronal subtype specification, maturation and maintenance. PloS one 113 19997604
2009 DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome. Human molecular genetics 112 19218269
2006 REST in good times and bad: roles in tumor suppressor and oncogenic activities. Cell cycle (Georgetown, Tex.) 107 16929174
2005 No rest for REST: REST/NRSF regulation of neurogenesis. Cell 103 15907461
2009 Gene dysregulation in Huntington's disease: REST, microRNAs and beyond. Neuromolecular medicine 99 19458943
2016 Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks. Cell reports 95 26947066
2017 NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. Molecular psychiatry 87 28070121
2004 Activation of REST/NRSF target genes in neural stem cells is sufficient to cause neuronal differentiation. Molecular and cellular biology 87 15340064
1996 A Xenopus gene, Xbr-1, defines a novel class of homeobox genes and is expressed in the dorsal ciliary margin of the eye. Developmental biology 87 8626010
2016 Brain REST/NRSF Is Not Only a Silent Repressor but Also an Active Protector. Molecular neurobiology 76 26742529
2010 SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution. Human molecular genetics 76 20457675
2009 Functional diversity for REST (NRSF) is defined by in vivo binding affinity hierarchies at the DNA sequence level. Genome research 73 19401398
2015 The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases. eNeuro 69 26465007
2010 Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer. Oncogene 68 20697351
2003 The canonical Wnt pathway directly regulates NRSF/REST expression in chick spinal cord. Biochemical and biophysical research communications 68 14575694
2013 REST: an oncogene or a tumor suppressor? Trends in cell biology 67 23414932
2016 REST is a hypoxia-responsive transcriptional repressor. Scientific reports 66 27531581
2002 REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene promoter activation. Biochemical and biophysical research communications 60 11779185
2011 REST/NRSF governs the expression of dense-core vesicle gliosecretion in astrocytes. The Journal of cell biology 58 21536750
2021 Paternal age affects offspring via an epigenetic mechanism involving REST/NRSF. EMBO reports 57 33399271
2019 Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's disease patients. Neuroscience letters 57 30684677
1999 Knockout of REST/NRSF shows that the protein is a potent repressor of neuronally expressed genes in non-neural tissues. BioEssays : news and reviews in molecular, cellular and developmental biology 56 10376008
1994 Blood volume responses of men and women to bed rest. Journal of clinical pharmacology 56 8089254
2009 REST and the RESTless: in stem cells and beyond. Future neurology 55 19885378
2019 Automated exploration of gene ontology term and pathway networks with ClueGO-REST. Bioinformatics (Oxford, England) 54 30847467
2018 Skeletal muscle microvascular and interstitial PO2 from rest to contractions. The Journal of physiology 54 29288568
2003 REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor. Molecular and cellular biology 53 14645515
2016 REST regulation of gene networks in adult neural stem cells. Nature communications 50 27819263
2014 RE-1 silencing transcription factor (REST): a regulator of neuronal development and neuronal/endocrine function. Cell and tissue research 49 25092546
2013 Sex and vasodilator responses to hypoxia at rest and during exercise. Journal of applied physiology (Bethesda, Md. : 1985) 49 23823148
2012 NRSF/REST neuronal deficient mice are more vulnerable to the neurotoxin MPTP. Neurobiology of aging 48 22766071
2017 REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis. American journal of human genetics 46 28686854
2006 An NRSF/REST-like repressor downstream of Ebi/SMRTER/Su(H) regulates eye development in Drosophila. The EMBO journal 46 16763555
2021 Neuroinflammation induces synaptic scaling through IL-1β-mediated activation of the transcriptional repressor REST/NRSF. Cell death & disease 45 33589593
2006 Characterization of the REST/NRSF-interacting LIM domain protein (RILP): localization and interaction with REST/NRSF. Journal of neurochemistry 45 16417580
2023 Electron Transfer Beyond the Outer Membrane: Putting Electrons to Rest. Annual review of microbiology 44 37713456
2016 Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells. International journal of molecular sciences 43 27153061
2017 Stepwise assembly of functional C-terminal REST/NRSF transcriptional repressor complexes as a drug target. Protein science : a publication of the Protein Society 42 28218430
2004 Regulation of the cholinergic gene locus by the repressor element-1 silencing transcription factor/neuron restrictive silencer factor (REST/NRSF). Life sciences 39 15017977
2019 REST: An epigenetic regulator of neuronal stress responses in the young and ageing brain. Frontiers in neuroendocrinology 37 31004616
2015 TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation. Cell death and differentiation 36 25613376
2008 NRSF silencing induces neuronal differentiation of human mesenchymal stem cells. Experimental cell research 36 18570921
2010 Expression and functions of the repressor element 1 (RE-1)-silencing transcription factor (REST) in breast cancer. Journal of cellular biochemistry 35 20564196
2008 How much REST is enough? Cancer cell 35 18455121
2023 REST Is Not Resting: REST/NRSF in Health and Disease. Biomolecules 34 37892159
2007 Dual role of NRSF/REST in activation and repression of the glucocorticoid response. The Journal of biological chemistry 33 17984088
2006 Characterization of the nuclear targeting signal of REST/NRSF. Neuroscience letters 33 16442230
2022 High glucose and palmitic acid induces neuronal senescence by NRSF/REST elevation and the subsequent mTOR-related autophagy suppression. Molecular brain 32 35850767
2021 REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons. Aging cell 32 34520100
2017 Regulation of USP37 Expression by REST-Associated G9a-Dependent Histone Methylation. Molecular cancer research : MCR 32 28483947
2017 REST regulates the cell cycle for cardiac development and regeneration. Nature communications 32 29215012
2012 Rarely at rest: RNA helicases and their busy contributions to RNA degradation, regulation and quality control. RNA biology 32 23064154
2011 Ethanol-induced neurodegeneration in NRSF/REST neuronal conditional knockout mice. Neuroscience 32 21396985
2019 The deficiency of NRSF/REST enhances the pro-inflammatory function of astrocytes in a model of Parkinson's disease. Biochimica et biophysica acta. Molecular basis of disease 31 31706914
2019 REST/NRSF transcription factor is overexpressed in hippocampus of patients with drug-resistant mesial temporal lobe epilepsy. Epilepsy & behavior : E&B 30 30903955
2009 Alteration of NRSF expression exacerbating 1-methyl-4-phenyl-pyridinium ion-induced cell death of SH-SY5Y cells. Neuroscience research 30 19631241
2006 Molecular genetic analysis of the REST/NRSF gene in nervous system tumors. Acta neuropathologica 29 16823502
2024 Erianin induces ferroptosis in GSCs via REST/LRSAM1 mediated SLC40A1 ubiquitination to overcome TMZ resistance. Cell death & disease 28 39039049
2016 Interactomic analysis of REST/NRSF and implications of its functional links with the transcription suppressor TRIM28 during neuronal differentiation. Scientific reports 27 27976729
2014 NRSF: an angel or a devil in neurogenesis and neurological diseases. Journal of molecular neuroscience : MN 27 25479824
2006 Bed rest and myopathies. Current opinion in clinical nutrition and metabolic care 27 16778570
2020 mGluR5 regulates REST/NRSF signaling through N-cadherin/β-catenin complex in Huntington's disease. Molecular brain 26 32859226
2019 REST-DRD2 mechanism impacts glioblastoma stem cell-mediated tumorigenesis. Neuro-oncology 26 30953587
2019 News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology. International journal of molecular sciences 26 31905747
2012 Tryptophan hydroxylase 2 (TPH2) in a neuronal cell line: modulation by cell differentiation and NRSF/rest activity. Journal of neurochemistry 26 22958208
2011 REST: transcriptional and epigenetic regulator. Epigenomics 26 22126152
2021 REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion. eLife 25 34855580
2017 The Importance of REST for Development and Function of Beta Cells. Frontiers in cell and developmental biology 25 28286748
2015 Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology. Neuroscience 25 26211447
2015 The GPMDB REST interface. Bioinformatics (Oxford, England) 24 25697819
2009 Turning REST/NRSF dysfunction in Huntington's disease into a pharmaceutical target. Current pharmaceutical design 24 19751206
2001 REST acts through multiple deacetylase complexes. Neuron 22 11516389
2015 NRSF and BDNF polymorphisms as biomarkers of cognitive dysfunction in adults with newly diagnosed epilepsy. Epilepsy & behavior : E&B 21 26708060
2005 Amino acid supplementation for reversing bed rest and steroid myopathies. The Journal of nutrition 21 15987870
2021 REST is a major negative regulator of endocrine differentiation during pancreas organogenesis. Genes & development 20 34385258
2020 Home for a rest: stem cell niche of the postnatal growth plate. The Journal of endocrinology 20 32240983
2018 NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease. Brain sciences 20 30572571
2004 REST and peace for the neuronal-specific transcriptional program. Annals of the New York Academy of Sciences 20 15153425
2023 Nurses' Rest Breaks and Fatigue: The Roles of Psychological Detachment and Workload. Western journal of nursing research 19 37621023

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