How does RNA decay contribute to gene expression? Could the RNA decay rate be regulated on a molecular basis in order to control genetic traits?
Gene expression is typically measured as messenger RNA (mRNA) abundance, and changes in that abundance are usually attributed to transcription, or synthesis, of mRNA inside the cell. However,
RNA abundance is also influenced by its disposal, or degradation, but how degradation controls RNA abundance is not well understood.
“My research uses a plant model, Arabidopsis thaliana, a small mustard plant, and we found that mutants with defects in mRNA decapping proteins experienced abnormal cell growth,” says Leslie Sieburth, Professor of Biological Sciences at the U.
“Our curiosity about why the mutants showed such poor growth led us to discover another mRNA decay enzyme, which we call SOV. We noted in our publication, in 2010, that most eukaryotic genomes encode a very similar protein, including humans,” says Sieburth.
A few years later, in 2013, scientists studying a human disorder called Perlman syndrome discovered that it was caused by mutations in the same gene. The gene, SOV, is known as DIS3L2 in humans.
Perlman syndrome is a genetic disorder associated with overgrowth in the size of the body or a body part of infants. The condition is almost always fatal prior to birth. The disorder has been grouped with Renal cell carcinoma and an increased risk for Wilms tumor.
Starting in 2014, Sieburth investigated how mRNA decapping and SOV/DIS3L2 contribute to decay of all mRNAs using genome-wide approaches.
“A fruitful collaboration with Fred Adler, a professor of biology and mathematics at the U, one of his graduate students, Katrina Johnson, and my postdoc Reed Sorenson, identified the decay rates of more than 17,000 mRNAs, and the contributions from decapping and SOV/DIS3L2,” says Sieburth.
One unexpected discovery was that the mRNAs that decay the fastest use the mRNA decapping pathway. A second discovery was that Arabidopsis mutants lacking an active SOV initiate a feedback pathway where the mRNAs – that are normally degraded by SOV – switch decay pathways, decay faster, and are also transcribed faster.
The results were published in Proceedings of the National Academy of Sciences (PNAS) in 2018.
Research in the Sieburth laboratory is supported by four National Science Foundation (NSF) grants totaling nearly $2 million. The largest grant, titled, “The role of regulated degradation in controlling cytoplasmic mRNA levels,” focuses on mRNA decay pathways and enzymes, such as SOV. The funding will extend to 2020.
Sieburth recently received a new award funded through NSF’s Early-concept Grants for Exploratory Research (EAGER) program for her project, “Connecting RNA Molecular Kinetics to Developmental Regulation.”
Sieburth employs two undergraduate students, two graduate students – Alex Cummins and
Jessica Vincent – and one postdoctoral fellow, Reed Sorenson.
Sieburth’s continuing genetic studies could provide new perspectives to fundamental cellular processes that are important in cancer biology and birth defects in humans.
In addition to research, Sieburth also is implementing new curriculum in the School of Biological Sciences. She is currently teaching a new class designed specifically for first-year students. The course, Fundamentals of Biology, is one part of a class sequence that includes two lecture-type classes and two laboratory classes.
“I led a curriculum reform committee, and along with nearly everyone in the School, have spent the past two years designing these courses, reading the literature to identify the instructional methods that have proven to lead to deep learning, and pulling together instructional materials,” says Sieburth. “We are a few months into the class now, and it is exciting to see that the students are engaged and learning.”
Sieburth has three specific goals for the current NSF study, “The role of regulated degradation in controlling cytoplasmic mRNA levels.”
The first is to assess changes in mRNA decay rates in response to conditions where RNA abundance changes. Usually abundance changes are attributed to transcription, but few scientists have tested the contributions from RNA decay.
The second goal is to understand the feedback that occurs in SOV mutants in Arabidopsis.
Third, she wants to understand the basis for the wide range in mRNA decay rates, where half-life varies between 3.5 minutes and more than 24 hours.