Disease relevance of REST

• In this study, we found that many human medulloblastomas express significantly elevated levels of both myc oncogenes, regulators of neural progenitor proliferation, and REST/NRSF, a transcriptional repressor of neuronal differentiation genes [1].
• Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation [1].
• The neuron-restrictive silencer factor [NRSF (RE-1 silencing transcription factor/X box repressor)] is a transcriptional silencer, which we have previously implicated in deregulation of the vasopressin promoter in small cell lung cancer (SCLC) [2].
• Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat [3].
• Impairment of the RE-1-silencing transcription factor (REST) and REST-dependent genes in Down Syndrome (DS) neuronal progenitor cells and neurospheres has been published recently [4].

Psychiatry related information on REST

• MAIN OUTCOME MEASURES: Cognitive function tests (Reitan Trail Making A and B), Brief Assessment Index (a measure of depressed mood) and four subscales from the Sickness Impact Profile (Ambulation, Social Interaction, Sleep and Rest and Housework) [5].
• Trained interviewers administered trail-making tests (Trail A and B), Brief Assessment Index (a measure of depressed mood) and four subscales from the Sickness Impact Profile (Ambulation, Social Interaction, Sleep and Rest, and Home work) [6].
• When subjects made ballistic movements after Osc compared with Rest, peak velocity was higher (P = 0.02) and movement time shorter (P = 0.06), but there was no difference (P = 0.83) in motor reaction time (time between the onset of the first agonist burst and movement onset) [7].
• Test-Retest Reliability of Heart Rate Variability and Respiration Rate at Rest and during Light Physical Activity in Normal Subjects [8].
• Moral reasoning, measured by the Rest Defining Issues Test, correlated -.18 but not with self-esteem scores [9].

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].

References