Certain small RNAs called tDRs can be found inside and outside cells during stress responses to different diseases. The researchers created an atlas of stress signatures for tDRs that could be used as disease markers and identify new pathogenic pathways.
The body’s ability to respond to various types of stress is essential to the maintenance of health, and the failure of these adaptive stress responses can trigger or worsen many diseases. New research by researchers at Massachusetts General Hospital (MGH) and published in Advanced sciences reveals that cells often release certain RNA molecules called tDRs in response to stressors, and that different tDRs can serve as markers of cellular stress in different diseases.
“RNA molecules have long been known to be the messenger between DNA (the genetic code) and proteins (the functional molecules of the cell); however, the last decade has seen researchers discover new functions of RNAs that don’t translate into proteins — the so-called non-coding RNAs,” says lead author Saumya Das, MD, PhD, co-director of the Resynchronization and Advanced Cardiac Therapy Program at the MGH.
Das notes that there is a growing list of non-coding RNAs with diverse functions, and among these a new class of RNAs has been shown to come from the so-called transfer RNAs which normally function to help make proteins at from classical messenger RNAs. These RNAs, called small tRNA-derived RNAs (tDRs), appear to be generated when larger “parent” tRNAs are cut into smaller versions by stress-activated enzymes.
By studying a variety of human and rat cells under three stressors – nutritional deprivation, low oxygen, and oxidative stress – which are often present in many disease states, Das and his colleagues generated a comprehensive landscape of tDRs that can be found inside cells (cellular) and outside cells (extracellular) during different stress responses. They also discovered that key proteins called RNases are important for the generation and stability of extracellular tDRs.
“While tDRs play an important role in cellular functions, we also found that tDRs are released from cells where they can serve as markers of cellular stress in different diseases,” says lead author Guoping Li, PhD, medical instructor at MGH and Harvard Medical School. “We saw that different types of stress signals can affect cellular and extracellular tDRs in different cell types, and that there are ‘signatures’ of these stress signals.”
The team created an atlas of stress signatures for cellular and extracellular tDRs that can be used not only as indicators of disease, but also as a starting point for scientists wishing to study the roles of distinct tDRs in cancer, fibrosis and other conditions. Das and his colleagues focus on such a tDR and its role in kidney disease.
Study co-authors include Guoping Li, Aidan C. Manning, Alex Bagi, Xinyu Yang, Priyanka Gokulnath, Michail Spanos, Jonathan Howard, Patricia P. Chan, Thadryan Sweeney, Robert Kitchen, Haobo Li, Brice D. Laurent , Sary F Aranki, Maria I. Kontaridis, Louise C. Laurent, Kendall Van Keuren-Jensen, Jochen Muehlschlegel and Todd. Mr Lowe.
This work was supported by the American Heart Association and the National Institutes of Health.
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