A research team from the University of Eastern Finland and the University of Oxford says it has shown that small RNA molecules occurring naturally in cells, i.e., microRNAs, are also abundant in cell nuclei. Previously, microRNAs were mainly thought to be found in cytoplasm. The scientists also discovered that microRNA concentrations in cell nuclei change as a result of hypoxia.

The findings strongly suggest that microRNAs play a role in the expression of genes in the cell nucleus, according to the scientists, who add that this observation is crucial for the development of novel gene therapy, among other things. Their study (“Changes in nuclear and cytoplasmic microRNA distribution in response to hypoxic stress”) appears in Scientific Reports.

The scientists profiled the division of microRNAs in different parts of endothelial cells, discovering that a large share of microRNAs is enriched in cell nuclei. When the scientists exposed the cell culture to hypoxia, they noticed that changes in the concentrations of individual microRNAs mostly took place either in cytoplasm or in the cell nucleus. This profiling study is the first one of its kind, showing that microRNAs play a more central role in regulating the expression of genes in cells than previously thought, noted the researchers. For instance, the scientists found that microRNA-210, a molecule previously strongly associated with hypoxia, is in fact especially abundant in the cell nucleus. This observation sheds light on previously unknown mechanisms that cells use to adapt to hypoxia.

MicroRNAs (miRNAs) are small noncoding RNAs that have well-characterized roles in cytoplasmic gene regulation, where they act by binding to mRNA transcripts and inhibiting their translation (i.e., post-transcriptional gene silencing, PTGS). However, miRNAs have also been implicated in transcriptional gene regulation and alternative splicing, events that are restricted to the cell nucleus,” the investigators wrote.

“Here we performed nuclear-cytoplasmic fractionation in a mouse endothelial cell line and characterized the localization of miRNAs in response to hypoxia using small RNA sequencing. A highly diverse population of abundant miRNA species was detected in the nucleus, of which the majority (56%) was found to be preferentially localized in one compartment or the other. Induction of hypoxia resulted in changes in miRNA levels in both nuclear and cytoplasmic compartments, with the majority of changes being restricted to one location and not the other. Notably, the classical hypoxamiR (miR-210-3p) was highly up-regulated in the nuclear compartment after hypoxic stimulus.

“These findings reveal a previously unappreciated level of molecular complexity in the physiological response occurring in ischemic tissue. Furthermore, widespread differential miRNA expression in the nucleus strongly suggests that these small RNAs are likely to perform extensive nuclear regulatory functions in the general case.”

MicroRNAs weaken the expression of their target genes by binding to the ends of their messenger RNAs in cytoplasm. This phenomenon is known as RNA interference, the discovery of whose mechanisms was recognized with a Nobel Prize in 2006.

At the University of Eastern Finland, Mikko Turunen, PhD, and colleagues demonstrated ten years ago that synthetic microRNA molecules can regulate genes of therapeutic importance in animal models by targeting their impact on genes’ regulatory areas in cell nuclei. This discovery, along with subsequent research, led the scientists to assume that structurally similar microRNAs occurring naturally in cells also play a role in the regulation of genes in the cell nucleus.

“It is highly significant that these microRNAs targeting the cell nucleus can also increase the expression of genes, which is opposite to what happens in RNA interference. This is a very important finding in view of novel gene therapy, for example,” said Turunen.

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