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:
Moissiard G, Cokus SJ, Cary J, Feng S, Billi AC, Stroud H, Husmann D, Zhan Y, Lajoie BR, McCord RP, Hale CJ, Feng W, Michaels SD, Frand AR, Pellegrini M, Dekker J, Kim JK, Jacobsen SE. MORC family ATPases required for heterochromatin condensation and gene silencing. Science. 2012 Jun 15;336(6087):1448-51. Epub 2012 May 3
Rajakumara E, Law JA, Simanshu DK, Voigt P, Johnson LM, Reinberg D, Patel DJ, Jacobsen SE. A dual flip-out mechanism for 5mC recognition by the Arabidopsis SUVH5 SRA domain and its impact on DNA methylation and H3K9 dimethylation in vivo. Genes Dev. 2011 Jan 15;25(2):137-52.
Chodavarapu RK, Feng S, Bernatavichute YV, Chen PY, Stroud H, Yu Y, Hetzel JA, Kuo F, Kim J, Cokus SJ, Casero D, Bernal M, Huijser P, Clark AT, Krämer U, Merchant SS, Zhang X, Jacobsen SE, Pellegrini M. Relationship between nucleosome positioning and DNA methylation. Nature. 2010 Jul 15;466(7304):388-92. Epub 2010 May 30
Jacob Y, Stroud H, Leblanc C, Feng S, Zhuo L, Caro E, Hassel C, Gutierrez C, Michaels SD, Jacobsen SE. Regulation of heterochromatic DNA replication by histone H3 lysine 27 methyltransferases. Nature. 2010 Aug 19;466(7309):987-91. Epub 2010 Jul 14
Law JA, Jacobsen SE. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet. 2010 Mar;11(3):204-20.