|Professor of MCD Biology
B.S., Carnegie-Mellon University
Ph.D., University of Colorado, Boulder
Postdoctorate, Fred Hutchinson Cancer Research Ctr, Seattle, WA.
Regulation of Pre-mRNA Splicing and Analysis of Small RNA Function and Biogenesis
Alternative Splicing Regulation and mRNA Stability
Research in our laboratory is focused on the alternative splicing code; the sequences on the pre-mRNA and the protein factors that bind to them which regulate alternative splicing. We have focused on the identification of the cis splicing-regulatory elements, the trans-acting protein factors that bind them, and the mechanisms by which splicing is regulated. Our laboratory is using the powerful genetic, molecular biology and bioinformatics tools available for the nematode Caenorhabditis elegans to tackle this problem. A recent area of focus is the connection between alternative splicing and message stability. In about 1/3 of cases, alternative splicing yields an isoform with a premature stop codon; this isoform is unstable and subject to nonsense-mediated mRNA decay. We have identified many examples of alternative splicing factors whose own expression is regulated by alternative splicing coupled to nonsense-mediated decay. We are characterizing this process in C. elegans where we have uncovered a phenomenon in which the efficiency of nonsense-mediated decay can be developmentally regulated.
Small RNA Function in Ciliated Protozoans
Ciliated protozoans possess two types of nuclei; a transcriptionally silent micronucleus, which serves as the germ line nucleus, and a transcriptionally active macronucleus, which serves as the somatic nucleus. The macronucleus is derived from a new diploid micronucleus after mating, with epigenetic information contributed by the parental macronucleus serving to guide the formation of the new macronucleus. In the stichotrichous ciliate Oxytricha trifallax, the macronuclear DNA is highly processed to yield gene-sized nanochromosomes with an average length of 2200bp - most nanochromosomes encode only one gene and there are %7e20,000 genes in the organism. We recently started to use this system to study the role of small RNAs in the regulation of chromatin. We found that soon after mating of Oxytricha is initiated, abundant 27nt small RNAs are produced that are not present prior to mating. We performed next generation sequencing of these small RNAs and found that the 27nt RNA class derives from the parental macronucleus. These small RNAs are produced equally from both strands of macronuclear nanochromosomes, but in a non-uniform distribution along the length of the nanochromosome, with a particular depletion in the 30 nt telomere-proximal positions. We are currently studying the mechanism by which the entire macronuclear genome is transcribed and processed into short RNAs and the role of these "27macRNAs" in macronuclear development.
Please follow this link to find the lab's publications in the National Library of Medicine's PubMed database.