I. Individual Variation in Gene Expression
II. It’s in Our RNA: A Study of the RNA-DNA Differences
III. Mechanisms that Underlie RNA Editing and RNA-DNA Differences
Part I: Individual Variation in Gene Expression
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Variations in gene expression generate much of the biodiversity we observe in nature. Dr. Vivian Cheung employs a genetic approach to identify regulators that influence expression levels of genes. By treating gene expression levels as quantitative traits, her laboratory was able to correlate DNA variants with gene expression levels. This analysis revealed cis- and trans-acting gene regulators such as DNA demethylase KDM4C, a master regulator of a subset of genes that control growth and apoptosis.
By sequencing and systematically comparing the DNA and RNA of individuals, the Cheung laboratory discovered thousands of sites where the RNA was different from its corresponding DNA sequence. Although other forms of RNA editing have been reported before, this report showed RNA-DNA differences (RDDs) that couldn’t be explained by previous mechanisms. Cheung’s laboratory characterized these RDDs and showed that these changes in the RNA were permanent and could result in a different protein.
In her third talk, Cheung overviews the molecular mechanisms that lead to RNA editing and other forms of RDDs. Her laboratory showed that the deaminase ADAR binds to a specific motif of the RNA to mediate A- to G- editing. In the other hand, they showed that RDDs are formed 60-100 nucleotides outside the polymerase bubble, which perfectly time with the formation of R-loops, a hybrid between the template DNA and the nascent RNA during transcription. A mutation that results in an overactive senataxin, a helicase that resolves R-loops, causes a rare form of amyotrophic lateral sclerosis (ALS). Cheung’s group showed that the increased helicase activity that resulted from senataxin mutation correlates with a decrease in R-loops in these patients and therefore a decrease in RDDs.
Dr. Vivian Cheung is a professor of genetics at the University of Michigan and a Howard Hughes Medical Institute investigator. Cheung obtained a bachelor’s degree in microbiology at the University of California, Los Angeles and graduated from Tufts School of Medicine. She continued her medical training as a pediatric resident at UCLA, and completed a neurology fellowship at The Children’s Hospital of Philadelphia.
Her laboratory uses molecular and computational methods to understand the genetic basis of human traits and diseases. Cheung wants to create genetic tools to improve preventive medicine and help better patient care. For her scientific contributions, Cheung was elected member of the National Academy of Medicine (2011), and received the Curt Stern Award in 2010. Learn more about Cheung’s research at her lab website.
- Robert Tjian iBioSeminar: The Molecular Biology of Gene Regulation
- Melissa Moore iBioSeminar: RNA Processing
- Anna Marie Pyle iBioSeminar: RNA Structure, Function and Recognition
- Phillip A. Sharp iBioMagazine: RNA Splicing: What is a Gene?
Juvenile amyotrophic lateral sclerosis (ALS4) website: https://www.als4.org/
Morley M, et al. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430: 743-747
Cheung VG, et al. (2005) Mapping determinants of human gene expression by regional and whole genome association. Nature 437: 1365-1369
Gregory BL & Cheung VG (2014) Natural variation in the histone demethylase, KDM4C, influences gene expression and cell growth. Genome Research 24:52-63
Cheung VG & Spielman RS (2009) Genetics of human gene expression: mapping DNA variants that influence gene expression. Nature Rev Genetics 10: 595-604
Parts II & III
Li M, et al. (2011) Widespread RNA and DNA sequence differences in the human transcriptome. Science 333: 53-58
Wang IX., et al. (2013) ADAR regulates RNA editing, transcript stability and gene expression. Cell Reports 14:849-60
Wang IX, et al. (2014) RNA-DNA differences are generated in human cells within seconds after RNA exits polymerase II. Cell Report 6: 906-915
Wang IX, et al. RNA-DNA sequence differences in Saccharomyces cerevisiae. Genome Research 26: 1544-1554