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Abstract
BackgroundA major role of REST (repressor element-1 silencing transcription factor) is to inhibit the expression of neuronal genes in neural stem cells and non-neuronal cells by binding to a 21 bp consensus sequence and recruiting epigenetic and regulatory cofactors to gene regulatory regions. In neural stem cells, REST silences differentiation-promoting genes to prevent their premature expression and is central to the regulation of neurogenesis and the balance of neural stem cells and neurons.ResultsTo understand the role of REST in vertebrate neurogenesis, we performed a genome-wide screen for REST targets in Xenopus tropicalis. We identified 742 neuron-restrictive silencer elements (NRSE) associated with 1396 genes that are enriched in neuronal function. Comparative analyses revealed that characteristics of NRSE motifs in frog are similar to those in mammals in terms of the distance to target genes, frequency of motifs and the repertoire of putative target genes. In addition, we identified four F-box ubiquitin ligases as putative REST targets and determined that they are expressed in neuronal tissues during Xenopus development.ConclusionWe identified a conserved core of putative target genes in human, mouse and frog that may be fundamental to REST function in vertebrates. We demonstrate that NRSE sites are associated with both protein-coding genes and lncRNAs in the human genome. Furthermore, we demonstrate that REST binding sites are abundant in low gene-occupancy regions of the human genome but this is not due to an increased association with non-coding RNAs. Our findings identify novel targets of REST and broaden the known mechanism of REST-mediated silencing in neurogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1591-4) contains supplementary material, which is available to authorized users.
Highlights
A major role of Repressor element silencing transcription factor (REST) is to inhibit the expression of neuronal genes in neural stem cells and non-neuronal cells by binding to a 21 bp consensus sequence and recruiting epigenetic and regulatory cofactors to gene regulatory regions
Identification of neuron-restrictive silencing element (NRSE) sites in the Xenopus tropicalis genome To identify NRSE sites in the X. tropicalis genome, we performed an in silico screen of the genome for a 17 bp degenerate NRSE consensus motif (NTYAGMRCCNNRG MSAG) generated from 32 bona fide REST target genes in human, rodents, and chicken [25,26]
Whereas nucleotide A is predominant at position 7 in the human NRSE consensus, both A and G are in high occupancy at this position in Xenopus (Figure 1A)
Summary
A major role of REST (repressor element-1 silencing transcription factor) is to inhibit the expression of neuronal genes in neural stem cells and non-neuronal cells by binding to a 21 bp consensus sequence and recruiting epigenetic and regulatory cofactors to gene regulatory regions. REST silences differentiation-promoting genes to prevent their premature expression and is central to the regulation of neurogenesis and the balance of neural stem cells and neurons. REST binds to a conserved 21-bp neuron-restrictive silencing element (NRSE) in the flanking regulatory regions or introns of many neuronal genes [3,4] and recruits the cofactors CoREST [5] and Sin3A [6] to form repressor complexes with histone deactylases [7], histone modifying proteins [8], the methyl-CpG-binding protein MeCP [9,10] and components of the SWI-SNF chromatin remodeling complexes [11]. The nuclear lncRNA, lncRNA_N1, physically interacts with REST during differentiation of hESCs (human embryonic stem cells) to promote neurogenesis [23]
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