The recent discovery of microRNAs (miRNAs) has revolutionized our understanding of gene control. Genetic studies in the nematode Caenorhabditis elegans (Figure 1) revealed the first members of what we now recognize as an extensive family of regulatory RNAs that exist in most multicellular organisms. Already there is evidence that specific miRNAs play key roles in controlling development, stem cell fates and neuronal differentiation, and mutations in human miRNA genes have been linked to oncogenic and other disease states. The Pasquinelli lab couples C. elegans genetics with molecular and biochemical techniques to understand the basic mechanisms of miRNA expression and function and to elucidate the biological roles of specific miRNAs in cellular differentiation programs.
How is the expression of miRNAs regulated? MiRNA genes typically encode long primary transcripts (pri-miRNAs) that undergo multiple processing steps to generate the mature ~22 nucleotide miRNA (Figure 2). Many miRNA genes are expressed at precise times in development and in specific tissues. To understand how these temporal and spatial expression patterns are achieved, we study the transcriptional and processing events that cooperate to produce specific miRNAs at the right time and in the right place.
How do miRNAs regulate gene expression? The miRNAs regulate specific genes by partially base-pairing to complementary sequences in the messenger RNAs (mRNAs) of protein-coding genes (Figure 2). The human genome contains over 700 different miRNA genes, each of which may directly regulate hundreds of protein coding genes. To help elucidate how miRNAs find and regulate targets with limited sequence complementarity, we have focused on specific miRNA genes and have performed genome wide analyses to identify potential targets. Regulation by miRNAs can result in degradation or translational repression of the target mRNA (Figure 2), but the molecular mechanisms behind these inhibitory strategies are not entirely understood. By studying defined miRNA and target pathways in C. elegans, my lab aims to elucidate how miRNAs control gene expression in the endogenous context.
What is the biological function of miRNA regulatory pathways? Some miRNA genes, like let-7, are essential for normal development (Figure 1). The let-7 miRNA and its temporally regulated expression pattern are widely conserved across animal phylogeny and misexpression of this miRNA has been linked to cancer in humans. A goal of our studies on the worm let-7 gene is to understand the broad role let-7 plays in cellular differentiation events across species.