Newly Discovered 'Chimeras' Influence Women's Health, Wellness

Strange “chimeric” RNA once thought to be the product of cancer is actually an important controller of women’s health, including influencing their susceptibility to infectious disease and autoimmune disorders, new University of Virginia School of Medicine research suggests.

UVA’s Hui Li, PhD, and colleagues have identified a chimeric RNA called UBA1-CDK16 that is found only in women. This RNA plays important roles in their blood cell development and in determining the severity of diseases such as COVID-19, the scientists found. The findings could open the door to blood tests to help diagnose diseases or identify women at greatest risk for bad outcomes.

“Chimeric RNAs are RNA molecules composed of parts from different genes,” said Li, of UVA’s Department of Pathology and the UVA Comprehensive Cancer Center. “They were once believed to be cancer-specific. However, our research shows that they can also be part of normal physiology and play important roles in human health.”

Powerful Chimeras

RNA provides instructions for our cells, telling them what to do based on the genetic material, called DNA, that we inherit from our parents. Chimeric RNAs were long thought to be mistakes, as they are made up of instructions mashed together from different genes. This is why they were believed to be a byproduct of cancer; cancer itself is the result of cellular copying mistakes.

Li’s discovery, however, suggests that UBA1-CDK16  plays important roles in maintaining women’s health and in controlling their immune systems. This chimeric RNA is found only in women because women have two X chromosomes, while men have an X and Y. Normally, one of the two X chromosomes found in women’s cells are inactive. But Li found that the inactive X chromosome produces this peculiar chimeric RNA that he could identify in women’s blood.

Based on his findings, Li believes UBA1-CDK16 plays an important role in regulating blood cell formation. But his work also suggests the chimera may play an important role in the immune system’s response to infection. He found that the chimeric RNA was lost in 50% women who developed severe COVID-19 infections, while it was present in women who were asymptomatic. Further, the decrease in chimeric RNA correlated with the increasing severity of the infection.

Li suspects that the chimeric RNA may play an important role in governing the development of immune cells called neutrophils that act as the body’s first responders to infection. (Neutrophil count has already been identified as a way to predict how patients will fare against COVID-19.) 

“As humans share similar number of genes with fruit flies and worms, gene number does not explain why we are much more sophisticated than these lower organisms” Li said. “We believe chimeric RNAs are another means to expand the functional genome, without an actual increase in gene number.”

Li’s findings suggest that the chimeric RNA also may serve as a natural brake to protect women from excessive autoimmune activity. Women are far more likely to suffer autoimmune disorders than men, and Li is urging additional research to better understand the role chimeric RNA could be playing – and how it could be targeted to improve patient outcomes.

“This finding highlights there is another layer of control for gene expression,” Li said. “These chimeric RNAs may represent a hidden repertoire for biomarkers and therapy targets as well.”

Findings Published

The researchers have published their findings in the scientific journal Science Advances. The research team consisted of Xinrui Shi, Loryn Blackburn, Sandeep Singh, Martyna Glowczyk-Gluc, Anam Tajamma, Shafaque Zahra, Shailesh Kumar, Robert Cornelison, Chen Liang, Fujun Qin, Aiqun Liu, Shitong Lin, Yue Tang, Justin Elfman, Thomas Manley, Timothy Bullock, Doris M. Haverstick, Peng Wu and Li. The scientists have no financial interest in the work.

The research was supported by the National Institutes of Health’s National Institute of General Medical Sciences, grant R01GM132128.

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