title: Regulation of neural macroRNAs by the transcriptional repressor REST.
abstract: The essential transcriptional repressor REST (repressor element 1-silencing transcription factor) plays central roles in development and human disease by regulating a large cohort of neural genes. These have conventionally fallen into the class of known, protein-coding genes; recently, however, several noncoding microRNA genes were identified as REST targets. Given the widespread transcription of messenger RNA-like, noncoding RNAs ("macroRNAs"), some of which are functional and implicated in disease in mammalian genomes, we sought to determine whether this class of noncoding RNAs can also be regulated by REST. By applying a new, unbiased target gene annotation pipeline to computationally discovered REST binding sites, we find that 23% of mammalian REST genomic binding sites are within 10 kb of a macroRNA gene. These putative target genes were overlooked by previous studies. Focusing on a set of 18 candidate macroRNA targets from mouse, we experimentally demonstrate that two are regulated by REST in neural stem cells. Flanking protein-coding genes are, at most, weakly repressed, suggesting specific targeting of the macroRNAs by REST. Similar to the majority of known REST target genes, both of these macroRNAs are induced during nervous system development and have neurally restricted expression profiles in adult mouse. We observe a similar phenomenon in human: the DiGeorge syndrome-associated noncoding RNA, DGCR5, is repressed by REST through a proximal upstream binding site. Therefore neural macroRNAs represent an additional component of the REST regulatory network. These macroRNAs are new candidates for understanding the role of REST in neuronal development, neurodegeneration, and cancer.
authors.affiliation: Genome Institute of Singapore, Singapore 138672. johnsonrb@gis.a-star.edu.sg
authors.forename: Rory
authors.initials: R
authors.lastname: Johnson
authors.forename: Christina Hui-Leng
authors.initials: CH
authors.lastname: Teh
authors.forename: Hui
authors.initials: H
authors.lastname: Jia
authors.forename: Ravi Raj
authors.initials: RR
authors.lastname: Vanisri
authors.forename: Tridansh
authors.initials: T
authors.lastname: Pandey
authors.forename: Zhong-Hao
authors.initials: ZH
authors.lastname: Lu
authors.forename: Noel J
authors.initials: NJ
authors.lastname: Buckley
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
authors.forename: Leonard
authors.initials: L
authors.lastname: Lipovich
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D004062:DiGeorge Syndrome / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D022661:RNA, Untranslated / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
chemical_list: D022661:RNA, Untranslated; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor