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Many long-noncoding RNAs (lncRNAs) regulate gene transcription by chromatin-associated processes such as chromatin looping, or recruitment or inhibition of chromatin-modifying enzymes. Yet to what extent the few well characterized examples are representative of the thousands of newly discovered and uncharacterized lncRNAs remains unknown. I examined the tightly-chromatin associated pool of lncRNAs in three different cell lines, and demonstrate between 50-60 pct. of lncRNAs are adhered to chromatin. I also discovered a distinct category of lncRNAs that are defined by especially tight chromatin-association. These chromatin-enriched lncRNAs (cheRNAs) are strongly correlated with the expression of neighboring genes, and transcriptional inhibition demonstrates functional enhancer roles for four cheRNAs. CheRNAs are remarkably cell-line specific, and are adjacent to genes with roles in defining the physiology of their respective tissue or cell lineages. I also demonstrate that cheRNA attachment to chromatin is mediated by stalled or active RNA polymerase, and present evidence that their evolutionary origin is linked to the spread of transposable elements. Collectively, cheRNAs are a subset of lncRNAs that may function in tissue-specific epigenetic regulation. In addition, I also described the biochemical nature of interaction between a lncRNA and its cognate protein partner WDR5 as being both specific and promiscuous, and define a plausible model to explain in vivo RNA-binding by chromatin-modifying enzymes.


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