Scott D. BriggsAssistant Professor of Biochemistry Investigators: Area: Role of histone methylation in gene expression and oncogenesis |
 |
In the eukaryotic cell, DNA is associated with protein factors to form chromatin. The fundamental repeating unit of chromatin is called the nucleosome where 146 base pairs of DNA is wrapped around two copies of each histone protein (H3, H4, H2A, and H2B). An important role for histone proteins is to help in the compaction of our genome into the nucleus of the cell. However, this compaction of DNA can restrict nuclear factors from gaining access to the DNA template. Therefore, somehow this inherently restrictive environment must be regulated and organized to allow permissive cellular processes such as gene transcription, replication, recombination, repair, and chromosomal segregation. One of the mechanisms that regulate chromatin structure and function is histone modifying complexes that posttranslationally modify histones. Generally, all of the histone modifications have been located on the N- and C-terminal tail domains (see figure). However, recent evidence has indicated novel modification sites within the central part of the histone called the histone fold-domain. Since posttranslational modifications on histones such as acetylation, phosphorylation, ubiquitination, and/or methylation can influence the chromatin environment and ultimately gene expression, we are interested in studying the machinery that mediates these modifications and how mis-regulation of these enzymes can lead to a disease state.
Histone methylation and regulation Recent work on histone methylation has lead to the identification of histone methylation sites and their corresponding methyltransferases. Histone methylation has now been identified on lysine (Lys) and arginine (Arg) residues on histone H3 and H4 (see figure). The catalytic core for some but not all lysine histone methyltransferases (HMTs) resides in the SET domain. A domain named for its appearance in Su(var) 3-9 (suppressor of position effect variegation), E(z) (enhancer of zeste), and Trx (trithorax). In contrast to lysine HMTs, arginine HMTs do not contain a SET domain but have highly conserved non-contiguous amino acid residues that are essential for forming its catalytic core. With the identification of these methyltransferases and their sites of methylation on histones, it is becoming clear methylation can organize chromatin into an active or repressed state. In pursuing this modification, my lab has largely exploited the strengths of yeast and mammalian model organisms in combination with biochemistry and molecular biology techniques. We are currently using budding yeast as a model system to understand how these methyltransferases are regulated and to determine their cellular functions. Methyltransferases and cancer Many SET domain-containing proteins have been associated with human cancers suggesting that they play an important regulatory roll in the cell. However, only a few have been identified as histone methyltransferases such as MLL1 and EZH2. Many of these SET domain-containing proteins are found either mutated, chromosomal translocated, or over-expressed when isolated from oncogenic cells. Therefore, we are interested in determining how mis-regulation and/or aberrant expression of these methyltransferases can lead to an oncogenic event and how aberrant histone methylation may play a role in oncogenesis. |
Selected Publications:
- Fingerman, I.M., Du, H.N. and Briggs, S.D. Histone methyltransferase assays. Cold Spring Harbor (CSH) Protocols. doi:10.1101/pdb.prot4939, 2008.
- Altaf, M., Utley, R.T., Lacoste, N., Tan, S., Briggs, S.D., and Côté, J. Interplay of chromatin modifiers on a short basic patch of histone H4 tail defines the boundary of telomeric heterochromatin. Molecular Cell. 28: 1002-1014, 2007.
- Fingerman I.M., Li H.C. and Briggs S.D. A charge-based interaction between histone H4 and Dot1 is required for H3K79 methylation and telomere silencing: Identification of a new trans-histone pathway. Genes Dev. 21: 2018-2029, 2007.
- Laribee R.N., Shibata Y., Mersman D.P., Collins S.R., Kemmeren P., Roguev A., Weissman J.S., Briggs S.D., Krogan N.J. and Strahl B.D. CCR4/NOT complex associates with the proteasome and regulates histone methylation. PNAS. 104: 5836-5841, 2007.
- Shi X., Kachirskaia I., Walter K.L., Kuo J.H., Lake A., Davrazou F., Chan S.M., Martin D.G., Fingerman I.M., Briggs S.D., Howe L., Utz P.J., Kutateladze T.G., Lugovskoy A.A., Bedford M.T. and Gozani O. Proteome-wide analysis in S. cerevisiae identifies several PHD fingers as novel direct and selective binding modules of histone H3 methylated at either lysine 4 or lysine 36. J. Biol. Chem. 282: 2450-2455, (2007).
- Bender L.B., Suh J., Carroll C.R., Fong Y., Fingerman I.M., Briggs S.D., Cao R., Zhang Y., Reinke V. and Strome S. MES-4, an autosome-associated histone methyltransferase that participates in silencing the X chromosomes in the C. elegans germ line. Development. 133, 3907-3917, (2006).
- Fingerman I.M., Wu C-L., Wilson B.D. and Briggs S.D. Global loss of Set1-mediated H3 Lys4 trimethylation is associated with silencing defects in Saccharomyces cerevisiae. J. Biol. Chem. 280: 28761-28765, (2005).
- Doun S.S., Burgner J.W., Briggs S.D. and Rodwell V.W. Enterococcus faecalis Phosphomevalonate Kinase. Protein Science. 14: 1134-9, (2005).
- Fingerman I.M. and Briggs S.D. P53-mediated transcriptional activation: from test tube to cell. Cell. Jun 11:117(6): 690-1, (2004).
- Rice J.C., Briggs S.D., Ueberheide B., Barber C.M., Shadanowitz J., Hunt D.F., Shinkai Y. and Allis C.D. Mammalian histone methyltransferases direct different degrees of histone H3 lysine 9 methylation to define distinct domains of silent chromatin. Mol. Cell. 12: 1591-1598, (2003).
- Milne T., Briggs S.D., Brock H.W., Gibbs D., Allis C.D. and Hess J.L. MLL targets SET methyltransferase activity to Hox gene promoters. Mol. Cell. 10: 1107-1117, (2002).
- Briggs S.D., Xiao T., Sun S.W., Caldwell J.A., Shabanowitz J., Hunt D.F., Allis C.D. and Strahl B.D. Trans-histone regulatory pathway in chromatin. Nature. 418: 498, (2002).
- Strahl B.D., Grant P.A., Briggs S.D., Sun Z.W., Bone J.R., Caldwell J.A., Mollah, S., Cook R.G, Shabanowitz J., Hunt D.F. and Allis C.D. Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol. Cell. Biol. 22(5): 1298-1306, (2002).
- Bryk M., Briggs S.D., Strahl B.D., Curcio M.J., Allis C.D. and Winston F. Evidence that Set1, a Factor Required for Methylation of Histone H3, Regulates rDNA Silencing in S. cerevisiae by a Sir2-Independent Mechanism. Curr. Biol. 12(2): 165-170, (2002).
- Briggs S.D., Bryk M., Strahl B.D., Cheung W.L., Davie J.K., Dent S.Y., Winston F. and Allis C.D. Histone H3 lysine4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes Dev. 15(24): 3286-3295, (2001).
- Strahl B.D., Briggs S.D., Brame C.J., Caldwell J.A., Koh S.S., Ma H., Cook R.G., Shabanowitz J., Hunt D.F., Stallcup M.R. and Allis C.D. Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1. Curr. Biol. 11(12): 996-1000, (2001).
