Kotaro Nakanishi, assistant professor of biochemistry, has received a new, five-year, $981,250 National Institutes of Health (NIH) RO1 grant from the National Institute of General Medical Sciences (NIGMS) to fund important research into gene regulation in humans, necessary for proper cell development and functioning.

The blueprint for protein is coded onto the genomic DNAs, which is copied into the messenger RNA (mRNA), which is translated into the protein. Depending on differentiation and development, each cell needs to change the pattern of protein synthesis. Humans have a system referred to as “RNA silencing” that degrades the cognate mRNAs to repress the synthesis of specific proteins. Due to its critical impact on human health, dysregulation of RNA silencing causes many diseases, including neurodegeneration and cancer.

“The key player of RNA silencing is a RNA-induced silencing complex,” Nakanishi explains. “This complex is composed of a short-length RNA called microRNA and a protein called Argonaute (AGO). The relationship between microRNA and AGO resembles that of a vinyl record and a turntable, respectively. To play the song engraved on itself, each record needs to be set on a turntable properly such that the groove is read out by the needle.”

Similarly, each microRNA needs to be loaded into AGO to read out the information about its target mRNAs written in itself. The AGO uses the information to bind to the target mRNAs and represses the protein synthesis. As a turntable can play different songs by setting different vinyl records on it, AGO can target different mRNAs by loading different microRNAs on it.

“Humans have four AGOs and more than 4,000 microRNAs. Imagine that you have four different types of turntables along with a collection of more than 4,000 vinyl records,” Nakanishi says. “You would be surprised if the four turntables play different songs even though the same vinyl record is set on them. You would think ‘no way.’ But — the impossible happens.” 

Recent studies showed that four AGOs target different mRNAs even though the same microRNA is loaded into them. How come? Nakanishi’s group has some clues now and will answer this question in the NIH-funded studies. The outcome of this research will provide a much better understanding of RNA silencing, which is essential to establish a sound basis for applications of the silencing system in therapeutics. 

Nakanishi’s lab also works on bioengineering projects, supported by a Center for RNA Biology Seed Grant and a graduate student’s Pelotonia Fellowship.