A library, wrote Victor Hugo, implies an act of faith. And so it is with a newly compiled library of human 3′-untranslated regions, or 3′-UTRs. Although this library of post-transcriptional regulatory elements is still being assembled, it is being presented as a resource that will help drug developers make sense of the tangled genetic pathways that can lead to disease. The library, its creators insist, has already led to the identification of potential gene-silencing approaches to the treatment of cancer and heart disease.
The new library, which aims to map the entire human 3′-UTRome, grew out of work initiated by Marco Mangone, Ph.D., a professor at Arizona State University and a research at the Biodesign Institute. Since his days as a doctoral student in Rome, Dr. Mangone has studied the production, function, and disease contributions of 3′-UTRs and their role in governing gene expression. He pioneered this work in a simple animal model, the worm C. elegans. Most recently, in work described December 9 in BMC Genomics, he has extended his purview to the human genome.
Dr. Mangone and colleagues presented a paper (“A human 3′UTR clone collection to study post-transcriptional gene regulation”) that describes the painstaking assembly of a library comprising 1,461 human 3′-UTRs cloned into Gateway entry vectors. These 3′-UTRs, which represent about 10% of the human genome, are freely available to the scientific community.
“[The library] contains 3′UTRs for 985 transcription factors, 156 kinases, 171 RNA binding proteins, and 186 other genes involved in gene regulation and in disease,” wrote the paper’s authors. “We demonstrate the feasibility of the h3′UTRome library by screening a panel of 87 3′UTRs for targeting by two miRNAs: let-7c, which is implicated in tumorigenesis, and miR-221, which is implicated in atherosclerosis and heart disease.”
The authors noted that after this screening exercise, the panel was enriched with genes involved in the RAS signaling pathway, putative novel targets for the two miRNAs, as well as genes implicated in tumorigenesis and heart disease.
This instance of faith rewarded moved the authors of the BMC Genomics paper to conclude that their library “can be utilized for high-throughput screens to identify regulatory interactions between trans-acting factors and 3′UTRs.” “Importantly,” the authors continued, “the library can be customized based on the specifications of the researcher, allowing the systematic study of human 3′UTR biology.”
The work of Dr. Mangone and colleagues is timely because many drug developers are seeking pairings of 3′-UTRs and microRNAs (miRNAs) that can block the transmission of unwanted genetic messages. In fact, the interplay between miRNAs and their specific URs has become a hot area in biology and the pharmaceutical industry. The global miRNA research market was valued at nearly $295.1 million in 2011, and it is expected to reach $763 million by 2017.
A broad portfolio of miRNA pathway drug candidates has been developed, some already in Phase II clinical trials, showing promising clinical data in different areas of medicine, such as cancer, HCV infection, and cardiovascular diseases.
Dr. Mangone ultimately seeks to map all the UTR targets for every miRNA, and to accelerate discovery, has made the first high-quality human 3'-UTRome library available to researchers worldwide. “Once we have this in place, we will be able to build the framework for understanding the underlying commonalities between gene networks,” said Dr. Mangone.