Chimeric RNA Once Seen as Cellular Junk Turns Out to Perform Essential Functions

A team at UVA Comprehensive Cancer Center has identified a surprising contributor to what is called the “G-value paradox.” Humans have no more protein-making genes than a tiny roundworm, yet our bodies and brains are far more complex. According to Hui Li, part of the answer may lie in “chimeric” RNA, molecules long dismissed as cellular junk. The work could also bear on breast cancer and other diseases.

According to Li’s findings, published recently in Science Advances, these RNAs are not useless debris. They can produce genetic instructions that extend our cellular blueprints past what genes alone provide, and they carry out essential tasks in healthy cells. The team also found that malfunctioning chimeric RNA helps drive the development of breast cancer. 

“We are getting better at finding chimeric RNAs, but we don’t know if they are just noise or functional meaningful,” said Li. “The work has led to the discovery of a large number of functional chimeric RNAs, some of which may play important roles in cancer.”

The name comes from the chimera of Greek mythology, a fire-breathing monster that merged a lion, a goat, and a serpent. Chimeric RNA likewise joins genetic material from two or more genes. Scientists initially took these molecules for accidents, material stitched together by mistake as cells followed their programming, or perhaps a product of cancer. Later work showed they are common in tissues throughout the body, and they came to be viewed as a normal part of physiology. Still, little was known about what any individual chimeric RNA does in healthy cells.

To close that gap, Li and his colleagues built a “prediction pipeline” for forecasting and evaluating the function of chimeras. They used it to assemble an atlas of more than 569,000 chimeric RNAs across 1,019 cancer cell lines. When the team removed chimeras from healthy cells, the normal cell cycle was disrupted and harmful changes reduced the cells’ ability to survive. Li concluded that chimeric RNAs serve a wide range of critical roles in vital cellular processes. The results “demonstrate that chimeric RNAs constitute a previously underappreciated layer of gene expression, expanding the functional genome beyond conventional genetics,” Li explained.

The atlas also showed that chimeric RNA frequently malfunctions in primary breast cancer tumors, and the team suspects chimera problems contribute to other cancers and diseases. Doctors have already developed treatments aimed at specific cancer-causing chimeras. By clarifying what chimeras do and how they might be targeted, the atlas could help move that strategy forward.