Rethinking RNA

Long-noncoding-RNAs

The discovery of a new class of noncoding RNA establishes a new paradigm for how we think about RNA in our cells. Credit biotiny.com

It’s a new day for RNA. In a study published in Cell Reports on Aug 18, Michael Werner, sixth-year graduate student in Cell and Molecular Biology, and Alex Ruthenburg, PhD, Neubauer Family Foundation Assistant Professor of Molecular Genetics and Cell Biology, detail their discovery of a new class of RNA molecule that could perhaps be considered the “dark matter” of the genome. They identified thousands of long noncoding RNAs that are physically attached to DNA (quite literally coating the genome), which may play important but yet unidentified roles in gene regulation. Werner describes his work in an article for Science Life.

Rethinking RNA
By Michael Werner

Michael Werner, 6th year graduate student in Cell and Molecular Biology

Michael Werner, 6th year graduate student in Cell and Molecular Biology

At some point in high school and college introductory biology classes you probably learned the “Central Dogma.” It posits that in all organisms, genetic information is coded within DNA, which is converted to a ‘messenger’ molecule called RNA, which is then converted into proteins – and it is proteins that perform the various functions of the cell as molecular machines. Advances in next-generation sequencing technologies during the last decade have revealed that this is only part of the story, however.

It turns out that only ~1.5 percent of our genome contains the information to make proteins. Most of the DNA in our genome is processed into RNA ‘transcripts’ that don’t code for proteins – referred to as noncoding RNA. Some have even been shown to perform functions in the cell as RNA molecules, without the need to be turned into a protein.

Ruthenburg

Alex Ruthenburg, PhD, Neubauer Family Foundation Assistant Professor of Molecular Genetics and Cell Biology

Now, together with Alex Ruthenburg, we’ve discovered a class of noncoding RNA that establishes a new paradigm for how we think about RNA in our cells. In our Cell Reports paper, we show that the majority of long noncoding RNA molecules are actually associated with DNA, as opposed to messenger RNAs that are loosely dispersed throughout the nucleus.

Remarkably, we identified several thousand RNAs that are actually physically tethered to DNA and coat the human genome, which we called chromatin-enriched RNAs (cheRNAs). The discovery of these RNAs was possible through biochemical enrichment of the genome, to the exclusion of other parts of the cell that predominately contained messenger RNA. Although we didn’t intend to find these cheRNA molecules, we decided to see if there was anything else we could learn about them.

To our excitement and considerable surprise, we found tantalizing hints that cheRNAs are involved in regulating the expression of nearby genes. The sheer number of these RNAs suggest that they could be a relatively common way to control genes throughout the human genome, possibly contributing to the complexity of tissues seen across our bodies.

The task ahead for our lab is now to determine the causality and molecular mechanism of cheRNAs in turning genes on, and whether this ‘dark-matter’ of the genome plays a role in development and disease. What’s certain, however, is that RNA is in no way just a messenger.

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The study “Nuclear Fractionation Reveals Thousands of Chromatin-Tethered Noncoding RNAs Adjacent to Active Genes,” was supported by the Chicago Biotechnology Consortium with support from The Searle Funds at The Chicago Community Trust and the Ellison Foundation.

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