Korean researchers uncover mechanism behind gene expression regulation for first time

Korean researchers have uncovered the protein assembly mechanism that regulates gene expression, paving the way for the precise design of RNA treatments — without side effects — for hard-to-treat diseases caused by excessive gene expression, including metabolic disorders and Alzheimer's disease.

The Ministry of Science and ICT announced Thursday that a joint research team led by Kim V. Narry, director of the Institute for Basic Science's RNA Research Center, and Noh Sung-hoon, a professor in the Department of Biological Sciences at Seoul National University, has identified the activation process of Argonaute, a protein that regulates gene expression, for the first time.

Argonaute is a protein that locates and eliminates unwanted genetic information inside human cells. It binds to microRNA, or miRNA, carrying the information to be removed, then tracks down and degrades the target messenger RNA, or mRNA. The findings, supported by the Ministry of Science and ICT, were published Thursday in Nature.

The research also has direct implications for the design of siRNA therapeutics — artificially synthesized miRNA that selectively blocks the activity of specific genes to prevent disease-causing proteins from being produced — a field that has long relied heavily on trial and error.

"This provides a molecular and theoretical basis for RNA therapeutic design, which until now has depended on trial and error," Kim said. "We expect it can be used to improve the efficiency of next-generation siRNA therapeutic design and applied to the treatment of a wide range of diseases, including genetic metabolic disorders."

Cells contain miRNA that suppresses excessive gene expression to maintain the body's balance. For miRNA to suppress gene expression inside a cell in practice, it must bind with an Argonaute protein to form a protein-RNA complex known as RISC. The process by which miRNA binds to Argonaute and becomes active had not previously been identified, limiting progress in RNA therapeutic development. To directly observe how Argonaute acquires gene-regulatory activity, the research team became the first in the world to isolate and purify an Argonaute complex bound to a chaperone, then used cryo-electron microscopy to analyze the complex's structure at the atomic level.