Dr. Steven Jacobsen and his colleagues are interested in cell memory, or the process by which dividing cells inherit states of gene activity. In particular, the researchers' work focuses on epigenetic modifications of chromatin, including cytosine DNA methylation and histone modifications. The researchers are using Arabidopsis thaliana as a model genetic system to study how these modifications function in gene silencing.
Much of the work stems from the discovery of a series of hypermethylated "SUPERMAN" (SUP) epigenetic alleles in Arabidopsis. These alleles are associated with dense methylation of the promoter and coding regions of the SUP gene and accompanied by a decreased level of SUP RNA. Jacobsen and his associates also found that a number of Arabidopsis mutants that decrease cytosine methylation, surprisingly, give rise to new hypermethylated sup alleles. This is superficially similar to a phenomenon found in many mammalian cancer cells which show overall genomic demethylation coupled with hypermethylation of specific tumor suppressor genes.
The researchers are utilizing these epigenetic alleles of SUP, and of a second gene involved in floral development called FWA, to study the genetics of gene silencing. The group's mutant screens have recently uncovered the major CpNpG DNA methyltransferase CMT3 and the major histone H3 Lysine 9 methyltransferase "KRYPTONITE," involved in gene silencing. The researchers also discovered that ARGONAUTE4 and siRNAs act to target both histone and DNA methylation, suggesting a link between RNAi and chromatin level gene silencing.
The other major project in Jacobsen's lab concerns the de novo DNA methyltransferase DRM2. He and his colleagues are using both genetics and biochemistry to work out the mechanisms by which cells initially recognize and silence genes.
Selected Cancer-Related Publications:
Bostick M, Kim JK, Estève PO, Clark A, Pradhan S, Jacobsen SE. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science. 2007; 317:1760-1764.
Zhang X, Yazaki J, Sundaresan A, Cokus S, Chan SWL, Chen H, Henderson IR, Shinn P, Pellegrini M, Jacobsen SE, Ecker JR. Genome-wide high-resolution mapping and functional analysis of DNA methylation in arabidopsis. Cell. 2006; 126:1189-1201.
Li CF, Pontes O, El-Shami M, Henderson IR, Bernatavichute YV, Chan SW, Lagrange T, Pikaard CS, Jacobsen SE. An ARGONAUTE4-containing nuclear processing center colocalized with Cajal bodies in Arabidopsis thaliana. Cell. 2006; 126(1): 93-106.
Tran RK, Henikoff JG, Zilberman D, Ditt RF, Jacobsen SE, Henikoff S. DNA methylation profiling identifies CG methylation clusters in Arabidopsis genes. Curr Biol. 2005; 15(2): 154-9.
Chan SW, Zilberman D, Xie Z, Johansen LK, Carrington JC, Jacobsen SE. RNA silencing genes control de novo DNA methylation. Science. 2004; 303(5662): 1336.
Jackson JP, Lindroth A, Cao X, Jacobsen SE. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature. 2002; 416:556-560.