Amy Pasquinelli

Research

The discovery that regulatory RNAs control almost every biological pathway has revolutionized our understanding of gene expression. At the forefront, microRNAs (miRNAs) have proven to be an abundant and essential class of RNA molecules in plants and animals. The numerous examples of defects in specific miRNA pathways contributing to complex diseases, including cancer, heart ailments and neuronal pathologies highlights the importance of these regulatory RNAs in human biology. The overall goal of the Pasquinelli Lab research program is to understand how miRNA-mediated regulation of gene expression contributes to organismal development and viability. We have primarily used C. elegans as a model animal system to investigate how miRNAs are expressed and regulate gene expression in an endogenous context. The pathways we study are broadly conserved throughout animal phylogeny and relevant to understanding the role of miRNAs in human development and disease.

A daunting challenge in the miRNA field is to establish biological functions for the thousands of miRNAs that have been discovered across species. While some miRNAs have proven to play essential roles in animal development, behavior, and viability, deficiencies in many other miRNAs appear to have no obvious consequences in worm or mouse knockout models. One explanation for these findings is that some miRNAs might only be needed in particular contexts, such as stress, that organisms regularly experience in the wild, but not in the laboratory. We use a combination of genetics, genomics, molecular biology and biochemistry to understand how the miRNA pathway responds to and regulates gene expression changes needed for an organism to survive environmental assaults, like high heat.

Another context where the miRNA pathway plays a key role is during organismal aging. MiRNAs depend on Argonaute (AGO) proteins to bind and regulate the expression of target genes at the post-transcriptional level. Surprisingly, we found that two AGOs play opposing roles in aging C. elegans. Loss of AGO Like Gene 1 (ALG-1) results in a shortened lifespan, while loss of ALG-2 leads to an extended lifespan. To understand the basis for these opposing longevity functions, we aim to identify the miRNAs, targets, tissues and aging pathways involved.