Topic Overview:
Human microRNAs have gained tremendous attention in both basic and clinical research over the past several years. While tales of microRNAs were just beginning to be told, an epic was being silently written with the 2006 discovery of 21U-RNAs in Caenorhabditis elegans, made possible by a revolutionary sequencing technology, called pyrosequencing. Such “next-generation” sequencing techniques, which can provide millions of sequences in a single run, enabled John to discover the presence of unusually small RNAs (usRNAs) in the human and Kaposi sarcoma-associated herpesvirus genomes. Approximately 30 percent of the thousands of usRNAs (which are even smaller than microRNAs) are likely to participate in important biological processes, including gene-silencing. The techniques John developed to study usRNAs led him to discover yet another class of small RNAs, which are found at the termini of genes and contain long poly(U) tails at their 5’ ends. These novel RNAs derive from both sense and antisense strands of known genes and are thought to be generated by an elusive RNA copying mechanism in humans. 

Although the various small RNA pathways are thought to be distinct, the John group has demonstrated that the pathways closely cooperate through either direct protein-protein interactions or transitive protein partners. Such interactions and other attributes common to small RNA pathways and other RNA processes―which, surprisingly, include splicing and transport mechanisms―illuminate the fundamentally important, intricate, and interlaced structure of the small RNA world. These discoveries, along with other emerging reports, point to a small RNA universe that extends far beyond the microRNA realm and raises the question: why do small RNAs exist? John hopes to build upon these observations to develop a new model, termed the “systems-to-systems hypothesis,” which will explain the observed specificity, efficacy, diversity, and importance of small RNAs.