How multiple RNA elements control MicroRNA biogenesis

26 May 2020

Two significant studies by a research team led by Dr Tuan Anh Nguyen (Croucher Innovation Award 2018), Assistant Professor in the Division of Life Science at the Hong Kong University of Science and Technology, have brought scientists a step closer to understanding how certain errors occur in a process called microRNA biogenesis, which could affect gene expression that, in turn, regulates various cellular functions.

Such errors are associated with a number of human diseases, including cancers and neurodegenerative diseases. Understanding how they occur can help scientists identify pathways for the development of therapies to correct such defects and thus treat the diseases.

To encode proteins, the genetic information found in our DNA is first converted into messenger RNA (mRNA) through a process called transcription. MicroRNAs (miRNAs) are small RNAs that do not encode proteins but play critical roles in regulating the stability of mRNAs and the translation of mRNAs to proteins.

As abnormal expression of miRNAs is often associated with diseases, having the ability to understand and manipulate the synthesis of miRNAs in cells is crucial to our being able to correct errors and provide treatments.

The focus for the research by Nguyen’s team was the process behind the expression of miRNAs, which must be strictly controlled to maintain their normal functions in cells. This involved further investigation of the human Microprocessor complex, which is responsible for cleaving primary miRNAs (also known as pri-miRNAs) to produce precursor miRNA (pre-miRNAs) and so ultimately determines the functions of miRNAs.

Nguyen had earlier made an essential contribution to understanding the Microprocessor complex while a postdoctoral researcher at the Seoul National University by overturning previous understanding on its cleaving mechanism to show that it worked more accurately as a combined effort of the complex’s two factors – DROSHA and DGCR8 – rather than DROSHA alone. This work was reported in two papers published in Cell in 2015 and 2016.

In his latest study, Nguyen and his team have discovered how RNA elements in the upper stem of pri-mRNAs affect the action of the Microprocessor complex. The findings were published in Nature Communications in April 2020.

While a number of RNA elements located in some parts of the pri-miRNA structure had been known to affect the processing of pri-miRNA by the Microprocessor, it had not been ascertained whether there were any RNA elements in the upper stem region of pri-miRNA that might affect the Microprocessor’s cleavage ability and hence subsequent cellular processes.

With the aid of high-throughput enzymology assays and next-generation sequencing technology, Nguyen and his team discovered multiple RNA elements in the upper stem of pri-mRNAs that are crucial for regulating the expression of various miRNAs in human cells.

The presence of these elements meant that when pri-mRNAs were cleaved by the Microprocessor, fewer products were made, or various alternative cleavage sites were generated instead of the original sites. These affected the expression level of the miRNAs, which resulted in dysregulation of the subsequent production of proteins from mRNAs, thus leading to abnormal human cell activities.

The work has enhanced understanding of the differential levels of miRNAs in diverse cellular processes and may help researchers interpret the cause of many miRNA-related human diseases, according to the team.

By specifically targeting the particular RNA elements identified by the team, it could also be possible to restore the normal levels of many abnormally expressing miRNAs in many miRNA-related disorders, potentially leading to the development of clinical miRNA-based diagnostics.

Earlier, Nguyen and his researchers published a paper in Nucleic Acids Research in March 2020 on their discovery of new RNA elements that control miRNA levels.

“We are currently using different approaches, including gene-editing technology, to modify the RNA elements we discovered in these two studies, in order to more accurately control the level of miRNAs in cellular systems,” he said. “The expected outcome from this study will be to lay the foundation for the future development of these RNA element-targeting therapeutics for miRNA-related diseases.”

Dr Tuan Anh Nguyen is originally from Vietnam. After graduation from Vietnam National University, he studied and completed his PhD in Biochemistry at the Korea Advanced Institute of Science and Technology (KAIST) in 2012. Subsequently, Nguyen moved to Seoul National University as a postdoctoral researcher. In 2017, he joined the Hong Kong University of Science and Technology as an Assistant Professor and started his lab in the Division of Life Science. The Nguyen lab aims to address the molecular mechanism of RNA-interacting proteins using biochemistry and bioinformatics approaches. He received his Croucher Innovation Award in 2018.

To view Tuan Anh Nguyen’s Croucher profile, please click here