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 DNAs 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 dont 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). Thats 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 havent been characterized yet, says Pier Paolo Pandolfi of Bostons Beth Israel Deaconess Medical Center. “We cant keep studying just two volumes of the book of life. We really need to study them all.”
Scientists no longer see the RNAs that arent 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 dont entirely understand. Take the chemotherapy drug cytarabine. Its 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 isnt 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”).
Coat of many colors
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 cats 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 tumors 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 peoples blood and tissues to determine if microRNAs can be used to help doctors better diagnose or understand conditions ranging from asthma and Alzheimers 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 cancers 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 instructions from being translated into proteins. One microRNA might have hundreds of mates, or targets, through which it influences many different body functions.
Lewis studies one gang of six microRNAs, known as the miR-17~92 cluster, the first group of microRNAs found to play a role in cancer. The six normally help strike a balance between cell growth and death, but an imbalance of these little molecules can push cells toward cancer.
Tumors in pancreatic cancer patients tend to have elevated levels of the cluster. To learn what the microRNAs were doing to goad cancer into taking hold, Lewis and colleagues used a genetic trick to remove the microRNAs from the pancreas in mice that were genetically engineered to develop pancreatic tumors. Early in their lives, mice with and without the microRNA cluster had about the same number of precancerous cells.
But by the time the animals were 9 months old, a clear difference emerged. In mice with the miR-17~92 microRNAs, nearly 60 percent of the pancreas was tending toward cancer, compared with less than 20 percent in mice lacking the cluster. The finding, reported in 2017 in Oncotarget, suggests that the microRNAs aid the cancers start.
The researchers developed bits of RNA that block some of the cluster members from spurring on the tumor. Using human pancreatic cancer cells grown in lab dishes, Lewis and colleagues found that taking out two of the six cluster members, miR-19a and miR-19b, stopped cancer cells from forming structures called invadopodia. As their name suggests, invadopodia allow tumors to break through blood vessel walls and other barriers to spread through the body.
Transfer RNA fragments
The virus helpers
For some young children and older adults, an infection with respiratory syncytial virus, or RSV, feels like a simple cold. But each year in the United States, more than 57,000 children younger than age 5 and about 177,000 people older than 65 are hospitalized because of the virus, the U.S. Centers for Disease Control and Prevention estimates. The infection kills hundreds of babies and about 14,000 adults over 65 annually.
Slightly higher than normal levels of some microRNAs had been linked to severe RSV infections. But molecular virologist Xiaoyong Bao of the University of Texas Medical Branch in Galveston wasnt convinced that modestly increasing amounts of a few microRNAs could really mean the difference between a child getting a slight cold and dying from the respiratory virus.
She consulted her Texas Medical Branch colleague, cancer researcher Yong Sun Lee, for advice on studying microRNAs. Lee said Bao would need to deeply examine, or sequence, RNA in cells infected with the virus. That was an expensive proposition in 2012 when Bao started the project. “But I squeezed from my [labs] dry bank account,” she says, to pay for the experiment. The investment paid off. Cells infected with RSV had more of one particular RNA than did uninfected cells. Surprisingly, it was a piece of a transfer RNA. Transfer RNAs, or tRNAs, are the assembly line workers of protein building. tRNAs read instructions in a messenger RNA and deliver the amino acids the ribosome needs to make a protein.
Scientists knew that working tRNAs are essential employees. Fragments, when they were found, were considered leftover bits of decommissioned tRNAs. But the fragments that Bao and colleagues discovered arent just worn out bits of tRNAs. Each fragment, about 30 bases long, is precisely cut from a tRNA when RSV infects cells. The fragments aid the viruss infection in more than one way. For instance, two fragments help the virus make copies of itself in cells, Bao and colleagues reported in 2017 in the Journal of General Virology.
tRNA fragments may also boost the bodys susceptibility to a virus. Last year, Baos group described in Scientific Reports how exposure to some heavy metals, via air or water pollution, can produce tRNA fragments that trigger inflammation, which may make people more susceptible to respiratory infections such as RSV.
Sacrificing infected cells
Another type of RNA may help protect against infection by certain viruses, including herpesvirus. Virologist Britt Glaunsinger has long marveled at the way viruses manipulate host cells by controlling RNAs in the cell. She became intrigued by transposons, mobile stretches of DNA that can jump from one location to another in the genome. Transposons make up nearly half of all the DNA in the human genome (SN: 5/27/17, p. 22). “We tend to think of [transposons] as parasites and things our own cells are constantly trying to shut down,” says Glaunsinger, a Howard Hughes Medical Institute investigator at the University of California, Berkeley. Thats because some are relics of ancient viruses. “While they may have initially Read More – Source