R Keith Slotkin
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R Keith Slotkin
B.S., University of Arizona
Ph.D., University of California Berkeley
Post-doctoral Research, Cold Spring Harbor Laboratory
Member of the Ohio State Center for RNA Biology
Member of the Molecular, Cellular and Developmental Biology Interdisciplinary Graduate Program (MCDB IGP)
Contact:
The Ohio State University
Plant Cellular and Molecular Biology
570 Aronoff Laboratory
318 West 12th Avenue
Columbus, OH 43210
Office: 614.292.1087
Laboratory: 614.292.1912
Fax: 614.292.6345
Send e-Mail to R Keith Slotkin
Focus:
My laboratory aims to discover how potentially mutagenic “jumping genes” or transposable elements are epigenetically repressed from generation to generation, as well as how this system has been adopted over evolutionary time to regulate non-transposable element genes.
Research Interests:
Transposable elements are stretches of DNA that can duplicate or move from one location in the genome to another. Their ability to replicate has resulted in transposable elements occupying vast amounts of most eukaryotic genomes, including nearly half of the human genome. Although often overlooked or dismissed as “junk DNA”, transposable elements have played an important role in the structure and evolution of the eukaryotic genome.
When transposable elements are active, they cause DNA damage and new mutations by inserting into essential protein-coding genes or by promoting rearrangements and genome instability. To suppress the inherent mutagenic potential of transposable elements, over a billion years ago eukaryotes evolved a genome-wide surveillance system to target transposable elements for inactivation. This process of selective inactivation takes advantage of the transposable element’s propensity to generate double-stranded RNA, which is the trigger for small RNA-based silencing mechanisms. These silencing mechanisms result in either post-transcriptional silencing or chromatin modifications. One such heritable chromatin modification is DNA methylation, which can be propagated from cell to cell (though mitosis) or from parent to progeny (through meiosis and fertilization). This heritable repression of gene expression is referred to as epigenetic regulation, and is not the result of changes in the primary DNA sequence (ATGCs). Epigenetic changes are distinct from genetic changes because they are readily reversible, making them exceptional targets of short-term or generation-to-generation environmental modulation.
For more information on the epigenetic regulation of transposable elements, see Slotkin and Martienssen, 2007, Nature Reviews Genetics.
My laboratory uses the model Arabidopsis thaliana (thale cress), a flowering plant, to investigate basic biological questions exploring how the eukaryotic genome and transposable elements interact over the development of a single generation, as well as across evolutionary time. Plants offer a unique opportunity to study transposable elements. Unlike animals, plants lack a germline that is set-aside early in embryonic development, meaning that epigenetic changes that occur during plant development are more likely to be transmitted to the next generation. Furthermore, plants have evolved a particularly diverse suite of mechanisms for encoding and propagating epigenetic modifications, such as forms of DNA methylation that specifically mark sites targeted by small RNA-based gene silencing. Finally, a wide variety of active transposable elements have been identified and examined in detail in plants.
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Studies into the location and timing of transposable element silencing in eukaryotes has led to the identification of germ cells as the key spatial and temporal point of the lifecycle where regulation occurs. Male germ cells (sperm cells) in flowering plants are housed in pollen grains. In Arabidopsis, mature pollen is a three-celled structure, containing two sperm cells embedded into a larger vegetative cell (see picture). Transposable element silencing is lost specifically in the pollen vegetative cell, resulting in the reactivation and mobilization of transposable elements. Because the pollen vegetative cell nucleus is essentially a somatic dead end, these active elements are not transmitted to the next generation. However, reactivated transposable elements from the vegetative cell do generate heritable information in the from of small RNA silencing signals trafficked into the sperm cells, which silence transposable elements in the germ cells. Thus it appears that the activation that occurs in the vegetative cell nucleus may serve as a mechanism to “unmask” potentially active transposable elements in order to reinforce their silenced state in the germ cells.
For more information on transposable element regulation in pollen, see Slotkin et al, 2009, Cell.
Projects in the laboratory focus on the following:
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How the cell recognizes which regions of the genome are genes and should be expressed, and which are transposable elements and should be selectively silenced
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How epigenetic information targeting transposable elements for silencing is propagated from generation to generation, protecting each generation from new mutations
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How the recruitment of epigenetic control to transposable elements has been co-opted over evolutionary time to produce novel and interesting examples of gene regulation
Selected publications (2003 - Date):
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2009 R. Keith Slotkin, Mathew Vaughn, Milos Tanurdzic, Filipe Borges, Jorg Becker, Jose Feijo and Robert Martienssen. Epigenetic reprogramming and small RNA silencing of transposable elements in pollen. Cell v136:461-472.
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2009 Kousuke Hanada, Veronica Vallejo, Kan Nobuta, R. Keith Slotkin, Damon Lisch, Blake Meyers, Shin-Han Shiu and Ning Jiang. Expression and Functional Indication of Pack-MULEs in Rice. The Plant Cell v21:25-38.
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2009 R. A. Martienssen, A. Kloc, R. Keith Slotkin and Milos Tanurdzic. Epigenetic Inheritance and Reprogramming in Plants and Fission Yeast. Cold Spring Harbor Symposium on Quantitative Biology, v73:265-271.
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2008 Milos Tanurdzic, Matthew Vaughn, H. Jiang, T.-J. Lee, R. Keith Slotkin, B. Sosinski, William F. Thompson, Rebecca F. Doerge and Robert A. Martienssen. Epigenomic Consequences of Immortalized Plant Cell Suspension Culture. PLoS Biology v6:e302.
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2008 Eyal Gruntman*, YiJun Qi*, R. Keith Slotkin*, Ted Roeder, Robert Martienssen and Ravi Sachidanandam. Kismeth: Analyzer of Plant Methylation States Through Bisulfite Sequencing. BMC Bioinformatics v9:e371.
*These authors contributed equally to this manuscript -
2007 R. Keith Slotkin and Robert A. Martienssen. Transposable elements and the epigenetic regulation of the genome. Nature Reviews Genetics v8:272-285.
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2005 R. Keith Slotkin, Michael Freeling and Damon Lisch. Heritable transposon silencing initiated by a naturally occurring transposon inverted duplication. Nature Genetics v37:641-644.
- 2003 R. Keith Slotkin, Michael Freeling and Damon Lisch. Mu killer causes the heritable inactivation of the Mutator family of transposable elements in Zea mays. Genetics v165:781-797.
Revised: 11-sep-09
