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Gene Review

REST  -  RE1-silencing transcription factor

Homo sapiens

Synonyms: NRSF, Neural-restrictive silencer factor, X2 box repressor, XBR
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Disease relevance of REST


Psychiatry related information on REST


High impact information on REST

  • In addition, we uncovered a previously unrecognized tumor suppressor role for REST/NRSF, a transcriptional repressor of neuronal gene expression [10].
  • The NRSE dsRNA can trigger gene expression of neuron-specific genes through interaction with NRSF/REST transcriptional machinery, resulting in the transition from neural stem cells with neuron-specific genes silenced by NRSF/REST into cells with neuronal identity that can express neuronal genes [11].
  • Many genes whose expression is restricted to neurons in the brain contain a silencer element (RE1/NRSE) that limits transcription in nonneuronal cells by binding the transcription factor REST (also named NRSF or XBR) [12].
  • These results indicate that NRSF recruits mSin3 and histone deacetylase 1 to silence neural-specific genes and suggest further that repression of histone deacetylation is crucial for transcriptional activation of neural-specific genes during neuronal terminal differentiation [13].
  • Transfection experiments using a series of NRSF deletion constructs revealed the presence of two repression domains, RD-1 and RD-2, within the N- and C-terminal regions, respectively [13].

Chemical compound and disease context of REST

  • METHODS: Rest and stress SPECT MPI and lipids were assessed serially in 25 patients (36% women) with CAD and dyslipidemia during the first six months of pravastatin therapy [14].
  • METHODS: Rest thallium (TI)-gated SPECT was performed with a 90 degrees dual-head camera, 4 h after injection of 185 MBq 201TI in 32 patients (mean age 61 +/- 11 y) with large myocardial infarction (33% +/- 17% defect on bull's eye) [15].
  • METHODS: Rest BMIPP, rest sestamibi and low-dose dobutamine echocardiographic studies were obtained in 18 patients 4 to 10 days after infarction (mean 6.7 +/- 2.0 days) [16].
  • Relaxation of glycine receptor and onconeural gene transcription control in NRSF deficient small cell lung cancer cell lines [17].
  • SUBJECTS AND METHODS: Rest and stress perfusion MRI studies were performed in 22 patients with coronary artery disease at 1.5 T using a multislice saturation recovery true FISP sequence after the bolus injection of 0.025 mmol/kg of body weight of gadopentetate dimeglumine [18].

Biological context of REST

  • The sequence defined by this dsRNA is NRSE/RE1, which is recognized by NRSF/REST, known primarily as a negative transcriptional regulator that restricts neuronal gene expression to neurons [11].
  • The transcriptional repressor REST/NRSF (RE-1 silencing transcription factor/neuron-restrictive silencer factor) and the transcriptional regulator REST4 share an N-terminal zinc finger domain structure involved in nuclear targeting [19].
  • Its cognate binding protein, REST/NRSF, is an essential transcription factor; its null mutations result in embryonic lethality, and its dominant negative mutants produce aberrant expression of neuron-specific genes [20].
  • REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor [19].
  • In contrast, when the cells were engineered to express a doxycycline-regulated REST/NRSF transgene (NSC-M-R), they no longer underwent terminal neuronal differentiation in vitro [1].

Anatomical context of REST

  • Together with earlier reports, these new findings suggest an important functional role for NRSF in the expression of the pax4 gene and infer a role for NRSF in pancreatic islet development [21].
  • To determine whether c-Myc and REST/NRSF act together to cause medulloblastomas, we used a previously established cell line derived from external granule layer stem cells transduced with activated c-myc (NSC-M) [1].
  • Overexpression of XBR in a B cell line resulted in a dramatic reduction of transcription from a reporter gene construct driven by the DPA promoter, but not from similar constructs with mutations in the X2 box [22].
  • A novel cDNA, termed XBR (X box repressor), encoding a putative zinc finger protein that binds specifically to the DPA X2 box was isolated from a human T cell line [22].
  • Similarly, overexpression of XBR reduced induction of reporter gene activity driven from the DPA promoter in HeLa cells treated with IFN-gamma [22].

Associations of REST with chemical compounds

  • METHODS: Rest and low dose dobutamine MRI was performed in 43 patients with a chronic infarct (> or =4 months since ischemic event) and LV dysfunction who had undergone revascularization of the infarct-related vessel [23].
  • MATERIALS AND METHODS: Rest-stress first-pass MR imaging with gadopentetate dimeglumine was performed in 17 patients with HCM and the Asp175Asn substitution in the alpha-tropomyosin gene and in five control subjects [24].
  • The area under the plasma glucose curve was 71% greater in Ex than in Rest (P = 0.01) [25].
  • DESIGN: Rest and exercise echocardiographies were performed prior to estradiol administration [26].
  • RESULTS: Rest wall motion score index (WMSI) was 2.2+/-0.3 and decreased to 1.9+/-0.41 after dipyridamole (p<0.001) [27].

Physical interactions of REST

  • Furthermore, NRSF and mSin3 formed a complex with histone deacetylase 1, suggesting that NRSF-mediated repression involves histone deacetylation [13].
  • This provides additional evidence that RILP interacts with REST/NRSF and REST4 in vivo, and is involved in the nuclear localization of REST/NRSF and REST4 [28].
  • Analyses of the SCLIP gene (approved symbol STMN3) show that it contains several NRSE-like elements that display low or no affinity for the cognate binding protein NRSF [29].

Other interactions of REST

  • This cis-activating NRSE element also confers NRSF-dependent modulation in the context of the native pax4 gene promoter [21].
  • These results show that RILP is required for REST/NRSF nuclear targeting and function [28].
  • Previous studies have shown that neither c-Myc nor REST/NRSF alone could cause tumor formation [1].
  • ANOVA was performed pixel by pixel to compute t (and z) for the task main effect (Verb vs Rest) in four different designs: (i) two way (subject and task) (2W), (ii) two-way with interaction (2WI), (iii) subject considered a random factor (2WI-MX), and (iv) three-way (subject, task, and replication) (3W) [30].
  • Direct interaction of NRSF with TBP: chromatin reorganization and core promoter repression for neuron-specific gene transcription [31].

Analytical, diagnostic and therapeutic context of REST

  • REST4 inhibited the binding of NRSF/REST to NRSE/RE-1 as determined by gel mobility shift assays [32].
  • Co-immunoprecipitation was used to demonstrate interaction between NRSF/REST and REST4 [32].
  • Regional cerebral blood flow was measured with positron emission tomography while subjects were at rest (Rest), read digits (Read), retrieved simple arithmetic facts from memory (i.e., 2 x 4, Retrieve), and performed mental complex calculation (i.e., 32 x 24, Compute) [33].
  • METHODS AND RESULTS: Rest and low-dose (5, 10 microg dobutamine x min(-1) x kg(-1)) multiplane dobutamine-TEE and ultrafast cine-MRI studies were performed in 103 patients [34].
  • The configural frequency analysis was computed with 3 continuous input variables: an electroencephalogram parameter, which represents the point of gravity of the EEG frequency distribution; the alpha slow-wave index, and the Rest Index, based on the presence or absence of phasic electromyographic activity [35].


  1. Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Su, X., Gopalakrishnan, V., Stearns, D., Aldape, K., Lang, F.F., Fuller, G., Snyder, E., Eberhart, C.G., Majumder, S. Mol. Cell. Biol. (2006) [Pubmed]
  2. A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: a potential role in derepression of neuroendocrine genes and a useful clinical marker. Coulson, J.M., Edgson, J.L., Woll, P.J., Quinn, J.P. Cancer Res. (2000) [Pubmed]
  3. Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat. Palm, K., Metsis, M., Timmusk, T. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  4. Transcription factor REST dependent proteins are comparable between Down syndrome and control brains: challenging a hypothesis. Sohn, S.Y., Weitzdoerfer, R., Mori, N., Lubec, G. J. Neural Transm. Suppl. (2003) [Pubmed]
  5. Quality of life of elderly patients with isolated systolic hypertension: baseline data from the Syst-Eur trial. Syst-Eur Trial Investigators. Fletcher, A.E., Bulpitt, C.J., Tuomilehto, J., Browne, J., Bossini, A., Kawecka-Jaszcz, K., Kivinen, P., O'Brien, E., Staessen, J., Thijs, L., Vänskä, O., Vanhanen, H. J. Hypertens. (1998) [Pubmed]
  6. Quality of life on randomized treatment for isolated systolic hypertension: results from the Syst-Eur Trial. Fletcher, A.E., Bulpitt, C.J., Thijs, L., Tuomilehto, J., Antikainen, R., Bossini, A., Browne, J., Duggan, J., Kawecka-Jaszcz, K., Kivinen, P., Sarti, C., Terzoli, L., Staessen, J.A. J. Hypertens. (2002) [Pubmed]
  7. Signs of muscle thixotropy during human ballistic wrist joint movements. Axelson, H.W. J. Appl. Physiol. (2005) [Pubmed]
  8. Test-Retest Reliability of Heart Rate Variability and Respiration Rate at Rest and during Light Physical Activity in Normal Subjects. Guijt, A.M., Sluiter, J.K., Frings-Dresen, M.H. Arch. Med. Res. (2007) [Pubmed]
  9. Correlations of self-ratings of attitude towards violent groups with measures of personality, self-esteem, and moral reasoning. Sotelo, M.J., Sangrador, J.L. Psychological reports. (1999) [Pubmed]
  10. A genetic screen for candidate tumor suppressors identifies REST. Westbrook, T.F., Martin, E.S., Schlabach, M.R., Leng, Y., Liang, A.C., Feng, B., Zhao, J.J., Roberts, T.M., Mandel, G., Hannon, G.J., Depinho, R.A., Chin, L., Elledge, S.J. Cell (2005) [Pubmed]
  11. A small modulatory dsRNA specifies the fate of adult neural stem cells. Kuwabara, T., Hsieh, J., Nakashima, K., Taira, K., Gage, F.H. Cell (2004) [Pubmed]
  12. Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Huang, Y., Myers, S.J., Dingledine, R. Nat. Neurosci. (1999) [Pubmed]
  13. Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes. Naruse, Y., Aoki, T., Kojima, T., Mori, N. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  14. Prospective serial evaluation of myocardial perfusion and lipids during the first six months of pravastatin therapy: coronary artery disease regression single photon emission computed tomography monitoring trial. Schwartz, R.G., Pearson, T.A., Kalaria, V.G., Mackin, M.L., Williford, D.J., Awasthi, A., Shah, A., Rains, A., Guido, J.J. J. Am. Coll. Cardiol. (2003) [Pubmed]
  15. Thallium-gated SPECT in patients with major myocardial infarction: effect of filtering and zooming in comparison with equilibrium radionuclide imaging and left ventriculography. Véra, P., Manrique, A., Pontvianne, V., Hitzel, A., Koning, R., Cribier, A. J. Nucl. Med. (1999) [Pubmed]
  16. Prediction of functional outcome after myocardial infarction using BMIPP and sestamibi scintigraphy. Franken, P.R., Dendale, P., De Geeter, F., Demoor, D., Bossuyt, A., Block, P. J. Nucl. Med. (1996) [Pubmed]
  17. Relaxation of glycine receptor and onconeural gene transcription control in NRSF deficient small cell lung cancer cell lines. Neumann, S.B., Seitz, R., Gorzella, A., Heister, A., Doeberitz, M.K., Becker, C.M. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  18. Detection of regional myocardial perfusion deficit using rest and stress perfusion MRI: a feasibility study. Fenchel, M., Helber, U., Kramer, U., Stauder, N.I., Franow, A., Claussen, C.D., Miller, S. AJR. American journal of roentgenology. (2005) [Pubmed]
  19. REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor. Shimojo, M., Hersh, L.B. Mol. Cell. Biol. (2003) [Pubmed]
  20. Transcriptional repression by neuron-restrictive silencer factor is mediated via the Sin3-histone deacetylase complex. Roopra, A., Sharling, L., Wood, I.C., Briggs, T., Bachfischer, U., Paquette, A.J., Buckley, N.J. Mol. Cell. Biol. (2000) [Pubmed]
  21. Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor. Kemp, D.M., Lin, J.C., Habener, J.F. J. Biol. Chem. (2003) [Pubmed]
  22. A zinc finger protein that represses transcription of the human MHC class II gene, DPA. Scholl, T., Stevens, M.B., Mahanta, S., Strominger, J.L. J. Immunol. (1996) [Pubmed]
  23. Dobutamine magnetic resonance imaging predicts contractile recovery of chronically dysfunctional myocardium after successful revascularization. Baer, F.M., Theissen, P., Schneider, C.A., Voth, E., Sechtem, U., Schicha, H., Erdmann, E. J. Am. Coll. Cardiol. (1998) [Pubmed]
  24. First-pass MR imaging in the assessment of perfusion impairment in patients with hypertrophic cardiomyopathy and the Asp175Asn mutation of the alpha-tropomyosin gene. Sipola, P., Lauerma, K., Husso-Saastamoinen, M., Kuikka, J.T., Vanninen, E., Laitinen, T., Manninen, H., Niemi, P., Peuhkurinen, K., Jääskeläinen, P., Laakso, M., Kuusisto, J., Aronen, H.J. Radiology. (2003) [Pubmed]
  25. Effect of prior exercise on glucose metabolism in trained men. Rose, A.J., Howlett, K., King, D.S., Hargreaves, M. Am. J. Physiol. Endocrinol. Metab. (2001) [Pubmed]
  26. The effects of sublingual estradiol on left ventricular function at rest and exercise in postmenopausal women: an echocardiographic assessment. Pines, A., Fisman, E.Z., Drory, Y., Shapira, I., Averbuch, M., Eckstein, N., Motro, M., Levo, Y., Ayalon, D. Menopause (New York, N.Y.) (1998) [Pubmed]
  27. The additive prognostic value of restrictive pattern and dipyridamole-induced contractile reserve in idiopathic dilated cardiomyopathy. Pratali, L., Otasevic, P., Rigo, F., Gherardi, S., Neskovic, A., Picano, E. Eur. J. Heart Fail. (2005) [Pubmed]
  28. Characterization of the REST/NRSF-interacting LIM domain protein (RILP): localization and interaction with REST/NRSF. Shimojo, M., Hersh, L.B. J. Neurochem. (2006) [Pubmed]
  29. Expression of stathmin family genes in human tissues: non-neural-restricted expression for SCLIP. Bièche, I., Maucuer, A., Laurendeau, I., Lachkar, S., Spano, A.J., Frankfurter, A., Lévy, P., Manceau, V., Sobel, A., Vidaud, M., Curmi, P.A. Genomics (2003) [Pubmed]
  30. Influence of ANOVA design and anatomical standardization on statistical mapping for PET activation. Senda, M., Ishii, K., Oda, K., Sadato, N., Kawashima, R., Sugiura, M., Kanno, I., Ardekani, B., Minoshima, S., Tatsumi, I. Neuroimage (1998) [Pubmed]
  31. Direct interaction of NRSF with TBP: chromatin reorganization and core promoter repression for neuron-specific gene transcription. Murai, K., Naruse, Y., Shaul, Y., Agata, Y., Mori, N. Nucleic Acids Res. (2004) [Pubmed]
  32. Regulation of cholinergic gene expression by the neuron restrictive silencer factor/repressor element-1 silencing transcription factor. Hersh, L.B., Shimojo, M. Life Sci. (2003) [Pubmed]
  33. Neural correlates of simple and complex mental calculation. Zago, L., Pesenti, M., Mellet, E., Crivello, F., Mazoyer, B., Tzourio-Mazoyer, N. Neuroimage (2001) [Pubmed]
  34. Head to head comparison of dobutamine-transoesophageal echocardiography and dobutamine-magnetic resonance imaging for the prediction of left ventricular functional recovery in patients with chronic coronary artery disease. Baer, F.M., Theissen, P., Crnac, J., Schmidt, M., Deutsch, H.J., Sechtem, U., Schicha, H., Erdmann, E. Eur. Heart J. (2000) [Pubmed]
  35. A taxonomic analysis of sleep stages. Müller, B., Gäbelein, W.D., Schulz, H. Sleep. (2006) [Pubmed]
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