Here are 5 RNAs that are stepping out of DNA’s shadow

Author: Tina Hesman Saey / Source: Science News

DNA is the glamour molecule of the genetics world. Its instructions are credited with defining appearance, personality and health.

And the proteins that result from DNA’s directives get credit for doing most of the work in our cells. RNA, if mentioned at all, is considered a mere messenger, a go-between — easy to ignore. Until now.

RNAs, composed of strings of genetic letters called nucleotides, are best known for ferrying instructions from the genes in our DNA to ribosomes, the machines in cells that build proteins. But in the last decade or so, researchers have realized just how much more RNAs can do — how much they control, even. In particular, scientists are finding RNAs that influence health and disease yet have nothing to do with being messengers.

The sheer number and variety of noncoding RNAs, those that don’t ferry protein-building instructions, give some clues to their importance. So far, researchers have cataloged more than 25,000 genes with instructions for noncoding RNAs in the human genome, or genetic instruction book (SN: 10/13/18, p. 5). That’s more than the estimated 21,000 or so genes that code for proteins.

Those protein-coding genes make up less than 2 percent of the DNA in the human genome. Most of the rest of the genome is copied into noncoding RNAs, and the vast majority of those haven’t been characterized yet, says Pier Paolo Pandolfi of Boston’s Beth Israel Deaconess Medical Center.

“We can’t keep studying just two volumes of the book of life. We really need to study them all.”

Scientists no longer see the RNAs that aren’t envoys between DNA and ribosomes as worthless junk. “I believe there are hundreds, if not thousands, of noncoding RNAs that have a function,” says Harvard University molecular biologist Jeannie Lee. She and other scientists are beginning to learn what these formerly ignored molecules do. It turns out that they are involved in every step of gene activity, from turning genes on and off to tweaking final protein products. Those revelations were unthinkable 20 years ago.

Back in the 1990s, Lee says, scientists thought only proteins could turn genes on and off. Finding that RNAs were in charge “was a very odd concept.”

Here are five examples among the many noncoding RNAs that are now recognized as movers and shakers in the human body, for good and ill.

Foiling cancer treatment

Sometimes anticancer drugs stop working for reasons researchers don’t entirely understand. Take the chemotherapy drug cytarabine. It’s often the first drug doctors prescribe to patients with a blood cancer called acute myeloid leukemia. But cytarabine eventually stops working for about 30 to 50 percent of AML patients, and their cancer comes back.

Researchers have looked for defects in proteins that may be the reason cytarabine and other drugs fail, but there still isn’t a complete understanding of the problem, Pandolfi says. He and colleagues now have evidence that drug resistance may stem from problems in some of the largest and most bountiful of the newly discovered classes of RNAs, known as long noncoding RNAs. Researchers have already cataloged more than 18,000 of these “lncRNAs” (pronounced “link RNAs”).

Beyond health and disease, noncoding RNAs play a role in appearance. One of the earliest examples of the power of overlooked RNAs: the multicolored coat of a calico cat. These felines’ mottled fur shows at least three lncRNAs in action, says Jeannie Lee, a molecular biologist at Harvard University. In female mammals, two lncRNAs team up to inactivate one copy of the X chromosome in each cell, while another lncRNA turns the other copy on (SN: 12/17/11, p. 22). The orange spots in a calico cat’s coat show where the lncRNAs have turned off the X chromosome gene responsible for making black fur. Black splotches show where the X chromosome containing the orange version of the gene has been inactivated. A different gene brings on the white fur.

Pandolfi and colleagues investigated how some lncRNAs may work against cancer patients who are counting on chemotherapy to fight their disease. “We found hundreds of new players that can regulate response to therapy,” he says.

When the researchers boosted production of several lncRNAs in leukemia cells, the cells became resistant to cytarabine, Pandolfi and colleagues reported in April 2018 in Cell. They also found that patients with AML who had higher than normal levels of two lncRNAs experienced a cancer recurrence sooner than people who had lower levels of those lncRNAs.

Researchers are just beginning to understand how these lncRNAs influence cancer and other diseases, but Pandolfi is hopeful that someday he and other researchers will devise ways to control the bad actors and boost the helpful ones.

Sparking a tumor’s spread

MicroRNAs are barely more than 20 RNA units, or bases, long, but they play an outsized role in heart disease, arthritis and many other ailments. These pipsqueaks can also lead to nerve pain and itchiness, researchers reported last year in Science Translational Medicine and in Neuron (SN Online: 8/13/18).

Hundreds of clinical studies are testing people’s blood and tissues to determine if microRNAs can be used to help doctors better diagnose or understand conditions ranging from asthma and Alzheimer’s disease to schizophrenia and traumatic brain injury. Some researchers are beginning to develop microRNAs as drugs and seeking ways to inhibit rogue microRNAs.

So far, the little molecules’ most firmly established roles are as promoters of and protectors against cancer (SN: 8/28/10, p. 18). Pancreatic cancer, for example, is a deadly foe. Only 8.5 percent of people are still alive five years after being diagnosed with this disease, according to U.S. National Cancer Institute statistics.

Cancer biologist Brian Lewis of the University of Massachusetts Medical School in Worcester and colleagues have learned that some microRNAs spur this lethal cancer’s initial attack and help the tumor spread from the pancreas to other organs.

MicroRNAs are mirror images of portions of the messenger RNAs that shuttle protein-making instructions from DNA to the ribosomes, where proteins are built. The microRNAs pair up with their larger messenger RNA mates and slate the bigger molecules for destruction, or at least prevent their…

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