CoREST: A functional corepressor required for regulation of neural-specific gene expression

Abstract

Several genes encoding proteins critical to the neuronal phenotype, such as the brain type II sodium channel gene, are expressed to high levels only in neurons. This cell specificity is due, in part, to long-term repression in nonneural cells mediated by the repressor protein REST͞NRSF (RE1 silencing transcription factor͞neural-restrictive silencing factor). We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for A large number of genes encoding neuronal phenotypic traits, including ion channels, neurotransmitters, synaptic proteins, and cell-adhesion molecules, are expressed only in neurons. One mechanism important in establishing and maintaining this neural specificity involves the DNA-binding protein REST͞ NRSF (RE1 silencing transcription factor͞neural-restrictive silencing factor) (1-4), which serves to block expression of its target genes in nonneural tissues. Such maintained gene repression is in contrast to the more dynamic repression mechanism that regulates inducible gene expression in response to steroid hormone receptors, one of the best-studied mammalian repressor mechanisms (for review, see ref. 5).One REST target gene essential for neuronal physiology is that encoding the brain type II voltage-dependent sodium channel. This ion channel is required for the propagation of fast electrical signals in neurons, in the form of neuronal impulses, and is not expressed in nonneural tissues. As is true for other REST target genes, there is a reciprocal relationship between expression of the type II sodium channel gene and expression of REST. Additionally, when a REST expression plasmid is cotransfected into neuronal cells along with a type II sodium channel reporter, the expression of the reporter gene is reduced dramatically (1). This result indicates either that REST alone is sufficient to repress its target genes or that REST accessory factors are present in neuronal cells despite the absence of REST.Two distinct repressor domains have been identified and characterized in REST (6, 7). These domains are located in the amino and carboxyl termini of the protein. Both domains are required for full repression in the context of the intact molecule, but each domain is sufficient to repress type II sodium channel reporter genes when expressed as a Gal4 fusion protein (6). The C-terminal repressor domain contains a C 2 H 2 class zinc finger beginning approximately 40 aa upstream of the stop codon. Deleting this domain, or introducing a point mutation critical to the zinc finger motif, abolishes repressor activity (6). Because zinc finger motifs often mediate proteinprotein interactions, we proposed that REST might function in conjunction with other nuclear factors or corepressors.In this study, we find that repression of the type II sodium channel promoter by REST requires a newly identified protein, CoREST, which fulfills the criteria for a bona fide corepressor. CoREST is a repressor; mutations that disrupt CoREST...

MicroRNA‐432 contributes to dopamine cocktail and retinoic acid induced differentiation of human neuroblastoma cells by targeting NESTIN and RCOR1 genes

“…RCOR1, target of miR-432, co-operating with transcriptional repressor REST and other transcription regulators silences expression of neuronal genes in non-neuronal cells and neural stem cells (NSCs) [52]. Recently, it has been shown that a large number of genes might be regulated by RCOR1 independent of REST.…”

Epigenetic Mechanisms in Stroke and Epilepsy

“…REST binds the RE1 element of target genes and recruits CoREST (Andres et al, 1999;Ballas et al, 2001) and mSin3A (Naruse et al, 1999;Huang et al, 1999;Grimes et al, 2000;Roopra et al, 2001), corepressor platforms which in turn recruit HDACs-1 and 2. HDACs deacetylate core histone proteins and affect dynamic and reversible gene silencing (Roopra et al, 2001;Ooi and Wood, 2007).…”

Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

“…However, equally important mechanisms controlling concurrent extrasynaptic down-regulation or repression of utrophin-A in myofibers that must occur to achieve expression at the NMJ rather than generalized expression throughout the sarcolemma remain unaddressed. Mechanistic clues arise from studies illustrating that restriction of neuronal sodium channel expression to the nervous system is partly due to RE-1 silencing transcription factor/neuronal-restricted silencing factor binding to a repressor element (Andres et al, 1999;Ballas et al, 2001;Lunyak et al, 2002). Additionally an N-box-mediated silencing mechanism has been suggested for nACHR subunit expression in extrasynaptic regions of muscle (Koike et al, 1995).…”