Pseudouridylation is the most widespread form of RNA epigenetic modification in living organizations, although the role of this process is poorly understood and little is known about how the modification of RNA molecules affects certain biological processes or how dysregulation of the process contributes to the development of disease in humans.
While investigating pseudouridylation, researchers at Sweden’s Lund University identified a previously unknown function of pseudouridine and identified a new mechanism that is used to control protein production and direct stem cell function.
Mature blood cells develop from hematopoietic stem cells and the process is sensitive to changes in protein levels. Even slight alterations to protein levels can have a negative effect on the development of new blood cells from stem cells.
The researchers identified a new control mechanism that is used to adjust the level of proteins necessary for hematopoietic stem cells to develop into blood cells. The team discovered stem cells that lacked an enzyme responsible for the pseudouridine modification to RNA resulted in the production of abnormal levels of protein which had a negative effect on stem cell growth into blood cells.
The enzyme PUS7 is capable of causing a pseudouridine modification to RNA and transforming it into a non-coding-protein RNA molecules. The presence of pseudouridine activates these non-coding-protein RNA molecules causing them to suppress protein synthesis, which ensures that the correct levels of protein are synthesized to support stem cell differentiation into blood cells.
Certain aggressive blood cancers are known to cause defective regulation of protein production, which results in dysfunctional stem cells. The discovery of this control mechanism could help improve understanding of the role of pseudouridine in human developmental disease and in blood cancers characterized by dysfunctional stem cells.
The research is detailed in the paper – Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells – recently published in the journal Cell.