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Study Finds LincRNAs Influencing Gene Expression in Human Cells

NEW YORK (GenomeWeb News) – A recently identified group of RNAs called large intergenic non-coding RNAs, or lincRNAs, can influence gene expression, apparently through interactions with chromatin-modifying complexes, according to a paper that's scheduled to appear online this week in the Proceedings of the National Academy of Science.

A team of Massachusetts researchers identified more than 1,700 new lincRNAs in six human cell lines. When they explored the interactions between these RNAs and chromatin-modifying proteins, they found that about a fifth of the known human lincRNAs bind to a chromatin-modifying complex called the polycomb repressive complex 2, or PRC2. This binding appears to obviate PRC2's repression of gene expression, suggesting the RNAs contribute to epigenetic control of the genome.

As such, at least some lincRNAs seem to act as "air traffic controllers" in the cell, directing chromatin modifications to the correct location on the genome, senior author John Rinn, a researcher affiliated with the Broad Institute and Beth Israel Deaconess Medical Center, told GenomeWeb Daily News.

Rinn and his co-workers identified the first lincRNA, HOTAIR, in 2007, showing that HOTAIR could influence gene expression by binding PRC2 and targeting it to the HOXD cluster where the polycomb cluster curbed HOXD gene expression.

Although they and others subsequently characterized a few other large non-coding RNAs, it wasn't until earlier this year that researchers realized just how widespread lincRNAs are in the mammalian genome. By focusing on a chromatin signature that's present in actively transcribed genes, Rinn and his co-workers identified nearly 1,600 lincRNAs in the mouse genome using chromatin state maps and other experiments.

For the latest study, the researchers used a similar method to learn more about the lincRNA repertoire in the human genome. But they also went a step further, looking at whether the newly found human lincRNAs were binding PCR2 or a few other chromatin-modifying proteins — and the consequences of these interactions.

Along with the 1,586 lincRNAs that are conserved between the mouse and human genome, the search turned up another 1,703 potential lincRNAs. The team concluded that most of these potential lincRNAs are likely genuine, based on custom tiling array experiments done to hone in on 1,147 of the loci.

While the new study more than doubles the number of known lincRNAs in the human genome, researchers say there are many more waiting to be discovered: they estimate that the human genome contains as many as 4,500 lincRNAs.

Since HOTAIR previously had shown to interact with the polycomb complex PRC2, Rinn explained, the researchers decided to look at which, if any, of the newly identified lincRNAs interacted with two PRC2 complex proteins — Suz12 and Ezh2 — using RNA co-immunoprecipitation, or RIP, in combination with microarrays in three different cell types.

The precise binding patterns varied by cell type. But, overall, almost a quarter of the lincRNAs tested physically interacted with PRC2 in at least one of the cell types. When they expanded their search, doing RIP-Chip for other proteins that modify chromatin to repress gene expression, the team reported that more than a third of the lincRNAs — about 38 percent — were associated with at least one of the repressive chromatin-modifying complexes tested.

And when the team individually knocked down six PRC2 complex-binding lincRNAs, including HOTAIR, they found that dialing back the expression of the lincRNAs increased the expression of hundreds of genes. These genes tended to overlap with those that are regulated by PRC2 and up-regulated in the absence of the complex, though the precise set of affected genes varied by lincRNA.

The changes in expression didn't seem to be a consequence of direct interactions between lincRNAs and messenger RNA, Rinn explained. "The next step is understanding how this is happening," he said.

The research is currently expanding on all fronts, Rinn noted, with the team working to tease apart the details of chromatin-RNA interactions. In addition, they are starting to sequence lincRNAs — and everything else — that's bound to the polycomb complex, mainly using Life Technologies' SOLiD and Illumina's sequencing platforms.

Even so, the researchers noted, the latest findings may represent just one sub-set of lincRNAs, since there are hints that the RNAs may be capable of carrying out other cellular functions as well. As such, the authors concluded, "The full range of biological diversity of lincRNAs and their mechanisms clearly remains to be explored."

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