RE1-Silencing Transcription factor (REST), also known asNeuron-Restrictive Silencer Factor (NRSF), is aprotein which in humans is encoded by theRESTgene, and acts as atranscriptional repressor.[5][6][7] REST is expressly involved in the repression of neural genes in non-neuronal cells.[7][8] Many genetic disorders have been tied to alterations in the REST expression pattern, including colon and small-cell lung carcinomas found with truncated versions of REST.[9] In addition to these cancers, defects in REST have also been attributed a role inHuntington's disease, neuroblastomas, and the effects of epileptic seizures and ischemia.
This gene encodes a transcriptionalrepressor which represses neuronal genes in non-neuronal tissues. It is a member of theKruppel-typezinc fingertranscription factor family. It represses transcription by binding a DNA sequence element called the neuron-restrictive silencer element (NRSE, also known as RE1). The protein is also found in undifferentiated neuronalprogenitor cells, and it is thought that this repressor may act as a master negative regulator ofneurogenesis.Alternatively spliced transcript variants have been described; however, their full length nature has not been determined.[5] REST is found to be down-regulated in elderly people withAlzheimer's disease.[10]
REST contains 8 Cys2His2 zinc fingers and mediates gene repression by recruiting severalchromatin-modifying enzymes.[11]
NRSF bound to DNA and cofactors on each of its two cofactor binding domains
Chromatin remodeling occurs, causing the gene to be 'turned off'
REST is also responsible for ischaemia induced neuronal cell death, in mouse models of brain ischaemia. Ischaemia, which results from reduced blood perfusion of tissues, decreasing nutrient and oxygen supply, induces REST transcription and nuclear accumulation, leading to the epigenetic repression of neuronal genes leading to cell death.[12] The mechanism beyond REST induction in ischaemia, might be tightly linked to its oxygen-dependent nuclear translocation and repression of target genes in hypoxia (low oxygen) where REST fulfils the functions of a master regulator of gene repression in hypoxia.[13]
^Ooi L, Wood IC (July 2007). "Chromatin crosstalk in development and disease: lessons from REST".Nature Reviews Genetics.8 (7):544–54.doi:10.1038/nrg2100.PMID17572692.S2CID415873.
Ooi L, Wood IC (July 2007). "Chromatin crosstalk in development and disease: lessons from REST".Nature Reviews Genetics.8 (7):544–54.doi:10.1038/nrg2100.PMID17572692.S2CID415873.
Palm K, Metsis M, Timmusk T (September 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.72 (1):30–9.doi:10.1016/S0169-328X(99)00196-5.PMID10521596.
Coulson JM, Edgson JL, Woll PJ, Quinn JP (April 2000). "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".Cancer Research.60 (7):1840–4.PMID10766169.
Kojima T, Murai K, Naruse Y, Takahashi N, Mori N (June 2001). "Cell-type non-selective transcription of mouse and human genes encoding neural-restrictive silencer factor".Brain Research. Molecular Brain Research.90 (2):174–86.doi:10.1016/S0169-328X(01)00107-3.PMID11406295.
Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E (September 2003). "Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes".Nature Genetics.35 (1):76–83.doi:10.1038/ng1219.PMID12881722.S2CID28110381.
