The long non-coding RNA Paupar regulates the expression of both local and distal genes

• Published in: The EMBO journal 2014-02, Vol.33 (4), p.296-311
• Main Authors: Vance, Keith W, Sansom, Stephen N, Lee, Sheena, Chalei, Vladislava, Kong, Lesheng, Cooper, Sarah E, Oliver, Peter L, Ponting, Chris P
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Cell Line, Tumor; CHART; Chromatin - metabolism; CNS; Conserved Sequence; EMBO36; EMBO44; Eye Proteins - biosynthesis; Eye Proteins - genetics; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Genes, cdc; Genome-Wide Association Study; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; lncRNA; Mice; Nerve Tissue Proteins - genetics; Neuroblastoma - pathology; Neurogenesis; Neurons - metabolism; Paired Box Transcription Factors - biosynthesis; Paired Box Transcription Factors - genetics; PAX6; PAX6 Transcription Factor; Protein Binding; Regulatory Elements, Transcriptional; Repressor Proteins - biosynthesis; Repressor Proteins - genetics; RNA, Long Noncoding - antagonists & inhibitors; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Long Noncoding - physiology; RNA, Small Interfering - pharmacology; transcription; Transcription, Genetic; Transfection
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/embj.201386225

Although some long noncoding RNAs (lncRNAs) have been shown to regulate gene expression in cis , it remains unclear whether lncRNAs can directly regulate transcription in trans by interacting with chromatin genome‐wide independently of their sites of synthesis. Here, we describe the genomically local and more distal functions of Paupar , a vertebrate‐conserved and central nervous system‐expressed lncRNA transcribed from a locus upstream of the gene encoding the PAX6 transcription factor. Knockdown of Paupar disrupts the normal cell cycle profile of neuroblastoma cells and induces neural differentiation. Paupar acts in a transcript‐dependent manner both locally, to regulate Pax6 , as well as distally by binding and regulating genes on multiple chromosomes, in part through physical association with PAX6 protein. Paupar binding sites are enriched near promoters and can function as transcriptional regulatory elements whose activity is modulated by Paupar transcript levels. Our findings demonstrate that a lncRNA can function in trans at transcriptional regulatory elements distinct from its site of synthesis to control large‐scale transcriptional programmes. Synopsis Paupar is a central nervous system‐expressed lncRNA that regulates the balance between proliferation and neuronal differentiation. Paupar controls target gene expression by binding regulatory elements near promoters, thus offering the first example of lncRNA‐mediated transcriptional regulation in trans. The conserved long non‐coding RNA Paupar is a novel regulator of neural growth and differentiation. Paupar functions in trans to regulate the expression of genes important for neural stem cell fate. Paupar binds and modulates the activity of multiple transcriptional enhancer and repressor elements located across different chromosomes. Paupar and PAX6 directly interact and co‐occupy a subset of Paupar binding sites. Graphical Abstract Paupar is a central nervous system‐expressed lncRNA that regulates the balance between proliferation and neuronal differentiation. Paupar controls target gene expression by binding regulatory elements near promoters, thus offering the first example of lncRNA‐mediated transcriptional regulation in trans.