CAREER: microRNA-mediated regulation of dosage sensitive genes involved in morphogenesis

Johns Hopkins University, Baltimore MD

Investigators

Abstract

The human genome has about 20,000 genes, which contain the information to produce proteins that carry out a myriad of functions in and around the cells that make up our bodies. For the correct development and function of human bodies, and those of any organism, specific proteins need to be produced in specific tissues or organs, at specific times. It is also essential that proteins be produced at their correct levels to achieve their normal cellular functions. A number of genes called “dosage sensitive genes” produce proteins that are exquisitely sensitive to changes in level, meaning that too much or too little of these proteins is detrimental to the cells, and thus to the living organism. Changes in the level of these proteins, which may be caused by having too few or too many copies of the genes that produce them, often result in human disease. This project studies a mechanism for ensuring that genes are not produced at overly high levels. The researchers study this type of regulation in a model organism that enables a quantitative and detailed examination of development and of protein production under different conditions. They use a microscopic nematode, C. elegans, in which they can modify genes and measure the output during development. Studying such mechanisms can inform our understanding of why some gene mutations cause disease, and could ultimately teach us how to manipulate gene dosage for therapeutic purposes. A significant fraction of genes in a genome are dosage sensitive, such that copy number variation (loss or gain of even a single genomic copy) often results in disease. Identifying the regulators that enable precise gene expression levels is critical to fully understand gene regulation and to reveal modifiers of disease relevant genes. MicroRNAs (miRNAs) are quantitative repressors of target mRNAs at the post-transcriptional level and it has been proposed that dosage sensitive genes rely on miRNA-mediated regulation. The researchers have established an experimental paradigm to test this in the context of a key developmental process that relies on precise gene dosage: animal morphogenesis. miR-100 is the most deeply conserved animal miRNA, present across all Eumetazoa. Despite its conservation, the molecular, cellular and organismal roles of miR-100 are practically unknown. The researchers propose to use C. elegans to study the function of this ancient animal miRNA and gain insight into the regulation of dosage sensitive genes in development. They have evidence that ECM components are conserved targets of miR-100 in worms, fish, mice and humans, suggesting that this miRNA may be involved in cellular signaling and adhesion in C. elegans, and likely other animals. Using genetic approaches, the researchers will reveal the role of this ancient miRNA in C. elegans, provide insight into its function in other animals based on shared targets, define the role of a dosage dependent regulator of morphogenesis, and gain new understanding of the contribution of miRNAs as regulators of dosage sensitive genes. This award is co-funded by the Developmental Systems Program in the Integrative Organismal Systems Division and the Genetic Mechanisms Program in the Molecular and Cellular Biosciences Division of the Directorate for Biological Sciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.