A New Puzzle Piece

Transfer RNAs (tRNA) (shown above) are noncoding RNAs that often get split into fragments. MCW scientists recently published the first study to demonstrate that tRNA fragments likely play a role in hypertension and kidney disease.

MCW scientists are the first to demonstrate a role for transfer RNA fragments in hypertension.

Scientists at MCW are shedding new light on the biological puzzle pieces that interact in hypertension and kidney disease, which may contribute to improvements in how these conditions are diagnosed and treated. Mingyu Liang, MB, PhD, PDF (postdoctoral fellow) ’02, Kohler Co. Professor in Cardiovascular Research, professor of physiology and director of the Center of Systems Molecular Medicine; Pengyuan Liu, PhD, adjunct professor of physiology; and their teams published results in the March 2021 issue of Hypertension from the first study to identify specific noncoding RNAs called transfer RNA (tRNA) fragments in rats and in preserved human kidney tissue from patient biopsies. The researchers also demonstrated that tRNA fragments likely play a role in hypertension and kidney disease that will need to be explored in more detail in future experiments.

“Our work is guided by the concept of molecular systems medicine. To continue advancing our understanding of human biology and disease, we need to define the genes, proteins and small molecules that make up a system, as well as determine how they interact with one another,” Dr. Liang says. He has been a proponent of a fundamental shift in biomedical research away from an overemphasis on individual molecules – which is reflected in his lab’s approach to studying RNA.

Among the RNA family, messenger RNAs, or mRNAs, are coding RNAs that carry the recipes for proteins directly from DNA in the cell’s nucleus to the cytoplasm where proteins are made. Dr. Liang and other epigenome experts have elevated the importance of noncoding RNAs over the last 10-15 years by discovering that these RNAs have significant effects on gene expression.

Dr. Liang’s lab has become one of the leading teams researching the influence of a form of noncoding RNA, called microRNA, in hypertension. As evidence continues to grow regarding the ability of noncoding RNA to enhance or diminish gene expression, Dr. Liang has turned his attention to tRNA fragments as a group that had not been studied previously by hypertension scholars.

“Transfer RNAs themselves are well-understood as they carry the building blocks of proteins – amino acids – to locations where proteins are being made, and are often cleaved into fragments. Little is known about what tRNAs do, especially in hypertension,” Dr. Liang notes. He and Dr. Liu hypothesized that tRNA fragments might alter gene expression in a similar fashion to microRNA, which binds to messenger RNA. Dr. Liang’s and Dr. Liu’s teams used next-generation RNA sequencing on four groups of salt-sensitive rats that are widely studied as a model for hypertension, as well as on kidney biopsy specimens from patients diagnosed with hypertensive kidney damage, and control patients. The scientists found more than 300 different tRNA fragments in rats and more than 150 different fragments in humans.

“In terms of defining another level of a molecular system, the volume of unique tRNA fragment types and the many copies of each fragment appear to be similar to the quantities of microRNA,” Dr. Liang adds.

In addition, the teams found that rats with hypertension caused by excessive salt consumption had different tRNA fragment levels than the control rats. A similar result was reported from the human kidney tissue biopsies from the patients with hypertensive kidney injury. The researchers also demonstrated that one of the tRNA fragments found in higher levels due to hypertension also alters gene expression by reducing the abundance of multiple messenger RNAs.

“Our findings have identified tRNA fragments as another important puzzle piece to study in hypertension as we continue to define larger molecular systems. There also is the potential that some of the fragments could be used to improve diagnostic methods or potentially become therapeutic targets for drug development,” Dr. Liang says.

– Greg Calhoun