'Junk RNA' molecule found to play key role in cellular response to stress

December 15, 2016, Massachusetts General Hospital
This is a computer graphic of an RNA molecule. Credit: Richard Feldmann/Wikipedia

A study from Massachusetts General Hospital (MGH) investigators has found a surprising role for what had been considered a nonfunctional "junk" RNA molecule: controlling the cellular response to stress. In their report in the Dec. 15 issue of Cell, the researchers describe finding that a highly specific interaction between two elements previously known to repress gene transcription—B2 RNA and EZH2, an enzyme previously known only to silence genes—actually induces the expression of stress-response genes in mouse cells.

"EZH2 is part of a structure called the Polycomb Repressive Complex 2, which silences target genes," says Jeannie T. Lee, MD, PhD,of the MGH Department of Molecular Biology, senior author of the report. "But a big paradox in the field has been that EZH2 is found at the sites of both active and inactive genes. We have shown, for the first time, that EZH2 can act outside of the PRC2 complex to activate genes through another mechanism—in this case by cleaving the B2 RNA molecule, which then activates stress response genes."

Less than 2 percent of the genome in mammals actually codes for proteins, and for many years it was thought that noncoding DNA was a useless artifact. While some is translated into RNA molecules required for maintaining and regulating cellular functions—such as transfer RNA and microRNAs - the impression that most noncoding RNA serves no function has persisted. This has been particularly true for long noncoding RNAs and is even more the case for molecules transcribed from "parasitic" retrotransposons—repetitive DNA sequences inserted throughout the genome. But recent studies in have indicated that RNA transcribed from the B2 retrotransposon binds to stress genes and suppresses their transcription.

Previous research by members of Lee's team found more than 9,000 nuclear transcripts that bind to EZH2. Data from that study also suggested that EZH2 interacted with some repetitive RNAs—including retrotransposon-transcribed RNAs—but at the time the association was not clear. The current study was designed to investigate whether that association was real and functional. Their cellular experiments confirmed that EZH2 binds to B2 RNA and, when subjected to heat, cuts or cleaves the RNA molecule. That cleavage of B2 RNA—which otherwise binds to and silences genes that protect against cellular damage by heat shock—allowed the transcription of those heat-shock genes.

"Our findings imply that B2 is a key regulator of the stress response and probably has that role in all types of cells," says Lee, who is a professor of Genetics at Harvard Medical School. "We and others have studied B2 cells in mice, but these same types of short interspersed nuclear elements are found in human cells, where they are quite different. While it remains to be seen whether human SINEs have similar properties, I wouldn't be surprised if they do."

Future studies will investigate the specific mechanism by which EZH2 is attracted to stress and how it cleaves the B2 RNA molecule. Since the both protects against some important diseases and is sometimes induced therapeutically—for example, to block the proliferation of cancer cells—improving the understanding of the is likely to make important contributions to human health.

Explore further: 'Junk' DNA now center stage

More information: Cell, DOI: 10.1016/j.cell.2016.11.041

Related Stories

'Junk' DNA now center stage

January 20, 2016

The classes of RNA molecules encoded by DNA sequences previously considered non functional may play a vital role in cell stress responses, and could one day lead to cancer treatments. A*STAR researchers have identified a ...

Protein predicts breast cancer prognosis

August 29, 2013

Researchers have identified a protein that they believe may help predict breast cancer prognosis, potentially relieving thousands of women at low risk from having to undergo painful, oft-debilitating therapies, while insuring ...

Jumping genes have essential biological functions

February 19, 2015

"Alu" sequences are small repetitive elements representing about 10% of our genome. Because of their ability to move around the genome, these "jumping genes" are considered as real motors of evolution. However, they were ...

Study identifies genetic variation in cellular stress

February 5, 2015

A new Cornell study examines how genetic differences among individuals impact cellular stress, a first step in understanding how this stress response relates to human diseases, such as diabetes.

Recommended for you

Built-in sound amplifier helps male mosquitoes find females

September 25, 2018

The ears of male mosquitoes amplify the sound of an approaching female using a self-generated phantom tone that mimics the female's wingbeats, which increases the ear's acoustic input by a factor of up to 45,000, finds a ...

Team discovers new species of dazzling, neon-colored fish

September 25, 2018

On a recent expedition to the remote Brazilian archipelago of St. Paul's Rocks, a new species of reef fish—striped a vivid pink and yellow—enchanted its diving discoverers from the California Academy of Sciences. First ...

Genome duplication drives evolution of species

September 25, 2018

Many wild and cultivated plants arise through the combination of two species. The genome of these so-called polyploid species often consists of a quadruple set of chromosomes—a double set for each parental species—and ...

Some female termites can reproduce without males

September 24, 2018

Populations of the termite species Glyptotermes nakajimai can form successful, reproducing colonies in absence of males, according to a study published in the open access journal BMC Biology.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.