Disease relevance of Rest

• The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells [1].
• They expressed the neuronal repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF; refs. 7-10) at very high levels compared with either neuronal progenitor NTera2 (NT2) cells or fully differentiated human neuron teratocarcinoma (hNT cells) [1].
• High-efficiency expression of REST-VP16 mediated by adenovirus vectors (Ad.REST-VP16) in medulloblastoma cells was able to counter REST/NRSF-mediated repression of neuronal promoters, stimulate expression of endogenous neuronal genes and trigger apoptosis through the activation of caspase cascades [1].
• The promoter regions of many Math5-dependent genes contained binding sites for REST/NRSF, suggesting that release from general repression in retinal progenitor cells is required for ganglion cell-specific gene activation [2].

High impact information on Rest

• These results indicate that NRSF is required to repress neuronal gene expression in vivo, in both extra-neural and undifferentiated neural tissue [3].
• The neuron-restrictive silencer factor NRSF (also known as REST and XBR) can silence transcription from neuronal promoters in non-neuronal cell lines, but its function during normal development is unknown [3].
• NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis [3].
• Mosaic inhibition of NRSF in chicken embryos, using a dominant-negative form of NRSF, also caused derepression of neuronal tubulin, as well as of several other neuronal target genes, in both non-neural tissues and central nervous system neuronal progenitors [3].
• Repressor element 1 (RE1)-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) can repress several terminal neuronal differentiation genes by binding to a specific DNA sequence (RE1/neuron-restrictive silencer element [NRSE]) present in their regulatory regions [4].

Biological context of Rest

• Within this 5' regulatory region, a putative neuron-restrictive silencer element conserved between rodent and human species was recognized and binds the neuron-restrictive silencing factor (NRSF/REST) [5].
• Ectopic expression, by viral gene transfer, of NRSF/REST in different insulin-secreting beta-cell lines induced a marked reduction in Cx36 mRNA and protein content [5].
• For optimal silencing of L1 gene expression by the NRSE-binding factor RE-1-silencing transcription factor (REST)/NRSF, both the NRSE and sequences in the first intron were required [6].
• Herein we have used a combined in silico and biochemical approach to identify binding sites [repressor element 1/neuron-restrictive silencer element (RE1/NRSE)] and potential target genes of RE1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) within the human, mouse, and Fugu rubripes genomes [7].
• The recombinant transcription factor REST-VP16 binds to the same DNA binding site as does REST/NRSF but functions as an activator instead of a repressor and can directly activate the transcription of REST/NRSF target genes [8].

Anatomical context of Rest

• Moreover, mutations in the Cx36 neuron-restrictive silencer element relieved the low transcriptional activity of the human CX36 promoter observed in HeLa cells and in INS-1 cells expressing NRSF/REST [5].
• Activation of REST/NRSF target genes in neural stem cells is sufficient to cause neuronal differentiation [8].
• The terminal differentiation of neuronal and pancreatic beta-cells requires the specific expression of genes that are targets of an important transcriptional repressor named RE-1 silencing transcription factor (REST) [9].
• Expression of transfected Crh-luciferase constructs was down-regulated by REST/NRSF in a RE-1/NRSE-dependent fashion in both muscle-derived L6 and REST/NRSF co-transfected neuronal PC12 cells [10].

Associations of Rest with chemical compounds

• Treatment of L6 cells with trichostatin A revealed that REST/NRSF repression depends, in part, on histone deacetylase activity in these cells [10].

Other interactions of Rest

• These experiments show that the NRSE and REST/NRSF are important components in restricting L1 expression to the embryonic nervous system [6].
• The resulting network model integrates post-transcriptional and translational controllers, including candidate feedback loops on NRSF and its corepressor, CoREST [11].

References