„Steersman“ for the regulation of gene activity

Microprocessor activity controls miRNA generation in the cell

October 09, 2014
Regulation of gene activity belongs to the most exciting areas of current genome research. Now, a research group of the Max Planck Institute for Molecular Genetics in Berlin managed to develop a method for studying an early step of the biogenesis of microRNA molecules in living cells. In the current issue of the journal Cell Reports the scientists headed by Ulf Ørom explain that the activity of the microprocessor complex is the most important step during the biogenesis of miRNA and can be used as a reliable measure for the amount of mature miRNAs in the cell.

microRNAs (miRNAs) are short, highly conserved RNA molecules, which are not translated into proteins, but play an important role for the regulation of gene activity. They bind to the messengerRNA (mRNA) of their target genes, thus inhibiting mRNA translation into proteins or even initiating their degradation. For a few years it has been known that formation of the primary miRNAs (pri-miRNAs) consisting of several hundreds of nucleotides is the first step during miRNA biogenesis. While still inside the nucleus, the microprocessor, a multi-protein complex, converts the pri-miRNAs into the precursor miRNAs (pre-miRNAs), which are only about 60 nucleotides long. The pre-miRNAs are actively transported out of the nucleus into the cytoplasm, where they are further processed into mature miRNAs. These bind to a huge complex of several proteins and nucleic acids, which specifically bind to mRNAs in the cytoplasm, thus inhibiting their translation into proteins.

Regulation of this very basic process in all cells of the organism is extremely complex. It has been known for some time that after microprocessor processing the activity of many miRNAs can be influenced during their transport into the cytoplasm as well as during their further processing into mature miRNA. In addition, it has been reported that even transcription of pri-miRNA molecules from the DNA is regulated in a tissue-specific manner. Now, scientists headed by Ulf Ørom from the Max Planck Institute for Molecular Genetics in Berlin have been able to show for the first time that regulation of miRNA biogenesis takes place especially during the microprocessor processing step.  The Berlin researchers developed a new approach to study the individual steps during the processing of pri-miRNA into pre-miRNA separately, in particular with regard to a quantity basis. They could show that no direct correlation between the number of transcribed pri-miRNA molecules and the activity of the microprocessor exists. On the other hand, they found a strong correlation between microprocessor activity and the amount of mature miRNA in the cell. The subsequent regulatory mechanisms during transport into the cytoplasm und processing of mature miRNA cannot countermand this fundamental dependence. For this reason, the scientists assume that the activity of the microprocessor is the most important step for the regulation of miRNA processing.

There is evidence that the activity of the microprocessor is also involved in pathological processes such as inflammation and cancer. The scientists hope their findings will contribute to a better understanding of the dysregulation of miRNA synthesis in disease and perhaps be a basis for the future development of suitable treatments.

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