Abstract
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.
Highlights
The resolution of two key questions would greatly improve our understanding of the functions of long noncoding RNAs
We found that mouse Paupar is most highly expressed in the adult brain (Fig 1D) and shows a clear correspondence in expression profile with Pax6 (Fig 1E)
While Paupar expression is undetectable in self-renewing embryonic stem (ES) cells, it is rapidly and transiently up-regulated after 1 day of retinoic acid (RA) treatment before increasing again at 4 days (Fig 1F), a profile similar to that observed for Pax6 (Fig 1G)
Summary
The resolution of two key questions would greatly improve our understanding of the functions of long noncoding RNAs (lncRNAs; ≥200 nucleotides). A number of lncRNAs have been shown to regulate transcription of neighbouring genes on the same chromosome in an apparent cis-acting mechanism (Lai et al, 2013; Melo et al, 2013; Wang et al, 2011). These lncRNAs appear to function near their site of synthesis, in either an RNA-dependent manner to mediate looping onto the promoter regions of their transcriptional targets, or by using RNA-independent mechanisms to locally alter chromatin status. LncRNAs have the potential to interact with chromatin and target multiple different loci genome-wide
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