Amy E. Pasquinelli

Scholar: 2004

Awarded Institution
Professor and Vice Chair
University of California, San Diego
Biology Department, Molecular Biology Section


Research Interests

The recent discovery of microRNAs (miRNAs) revolutionized our understanding of gene control and this new class of tiny regulatory RNAs was heralded as Science Magazine's 2002 Breakthrough of the Year. MiRNAs are present in organisms as diverse as plants, worms, flies and humans, where they are likely to be involved in regulating core processes such as development, growth and behavior. The founding members of this new class of tiny RNA genes were initially discovered through genetic studies in the nematode Caenorhabditis elegans as essential regulators of development (Fig. 1). Our lab couples C. elegans genetics with molecular and biochemical techniques to understand the mechanisms employed in this new form of gene regulation.

Fig. 1: C. elegans worms that contain mutations in the let-7 miRNA gene develop abnormally, often rupturing at the midsection. The let-7 miRNA is expressed in most animals, including humans, where it may also play an essential role in regulating development.

   How are miRNAs generated? Several miRNA genes are only expressed at precise times in development. We seek to understand how this transcriptional control is achieved. MiRNA genes encode precursor RNAs that undergo processing to the functional ~22 nucleotide forms (Fig. 2). Some of the factors that carry out RNA interference (a technique for targeting specific genes for down regulation) serve an endogenous role to generate mature miRNAs. We are interested in identifying additional proteins that recognize miRNA precursors and produce the functional forms.

   What do miRNAs do? Currently, we believe that miRNAs regulate gene expression by base pairing to complementary sequences in the messenger RNA (mRNA) of targets (Fig. 2). Because miRNAs can regulate mRNAs that contain imperfect antisense complementarity, the natural targets of the hundreds of new miRNAs are yet to be identified. Genetic studies in C. elegans have led the way in revealing the pathways and specific genes regulated by miRNAs and we continue to utilize this powerful system for understanding the function of these tiny RNA genes.

   How do miRNAs function? Antisense complementarity is a simple yet specific method for regulating gene expression. So far we know of a few examples where synthesis of a miRNA results in the inhibition of translation of specific mRNAs but the mechanism is yet to be understood. Moreover, the mode of regulation exerted by different miRNAs may vary depending on the position and type of base pairing structure formed when the miRNA recognizes its target (Fig. 2). We aim to determine the molecular mechanisms by which specific miRNAs control gene expression.

Fig. 2: Some miRNA genes cluster together in the genome and initially may be expressed as common primary transcripts that undergo processing to shorter hairpin RNAs. Specific protein factors, some of which function in RNAi, cleave the hairpins to the 22nt forms. The mature miRNAs base pair to mRNAs of protein coding genes to regulate their expression by unknown mechanisms.