Area of Expertise: Role of histone methylation in gene expression and
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, this inherently restrictive environment must be regulated
and organized to allow permissive cellular processes such as gene transcription,
replication, recombination, repair and chromosomal segregation. The mechanisms
that regulate chromatin structure and function are histone modifying complexes
that posttranslationally modify histones. Generally, all of the histone
modifications have been located on the N- and C-terminal tail domains. 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 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.
Posttranslational modifications on histones. Specific amino acid
sites of posttranslational modifications (acetylation, phosphorylation,
ubiquitination and methylation) that are known to occur on histones are
indicated by colored symbols. Half of the structure of the nucleosome core
particle H3 (yellow), H4 (blue), H2A (red) and H2B (green) are shown in
color. The other half is represented in grey.
Histone methylation and regulation
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 conserved
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. Histone lysine methylation is a unique posttranslational modification
since it can exist in three different methyl states (mono-, di- and trimethyl). In
S. cerevisiae, all three methylation states are catalyzed by the same
enzyme. For example, Set1, Set2 and Dot1 are responsible for catalyzing mono-,
di- and trimethylation on histone H3 at Lys4, Lys36, and Lys79,
respectively. Interestingly, histone methylation can organize chromatin into an
active or repressed state depending on the site of methylation and
methyl-binding protein. 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 Set1, Set2 and Dot1 methyltransferases and their sites of histone
Methyltransferases and cancer
Several histone methyltransferases and demethylases are found either mutated,
chromosomal translocated, or over-expressed when isolated from oncogenic
suggesting that they play an important regulatory role in the cell. 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. Therefore, understanding the
mechanism of how histone methyltransferases and demethylases function will
provide key insights into designing small molecule inhibitors for potential
novel chemotherapeutic drugs.
Awards & Honors
(2012) Kohls Outstanding Undergraduate Teacher Award for Biochemistry. Purdue University Department of Biochemistry.
(2011) Faculty Scholar. Purdue University.
(2010) Faculty Scholar. Purdue University.
(2006) Seed for Success. Purdue University.
(2004) Fellowship. Leukemia and Lymphoma Society.
(2004) Sidney Kimmel Scholar. Sidney Kimmel Foundation.
(2004) Walther Assistant Professor of Biochemistry. Walther Cancer Institute.
Briggs, S. D. (2000). Patent on the development of a histone methyl-specific antibody that recognizes histone H4 that is methylated at Arg3. U.S. Patent No. N/A. Washington, D.C.: U.S. Patent and Trademark Office.
South, P. F., Harmeyer, K. M., Serratore, N. D., & Briggs, S. D. (2013). H3K4 methyltransferase Set1 is involved in maintenance of ergosterol homeostasis and resistance to Brefeldin A. Proc. Natl. Acad. Sci. U.S.A., 11, E1016-E1025. Retrieved from http://www.pnas.org/cgi/pmidlookup?view=long&pmid=23382196
Mersman, D. P., Du, H. N., Fingerman, I. M., South, S. D., & Briggs, S. D. (2012). Charge-based interaction conserved within hisone H3 lysine 4 (H3K4) methyltransferase complexes is needed for protein stability, histone methylation, and gene expression. J. Biol. Chem., 287, 2652-2665. Retrieved from http://www.jbc.org/content/287/4/2652.full.pdf+html
Du, H. N., & Briggs, S. D. (2010). A nucleosome surface formed by histone H4, H2A, and H3 residues is needed for proper histone H3 Lys36 methylation, histone acetylation, and repression of cryptic transcription. J. Biol. Chem., 285, 11704-11713. Retrieved from http://www.jbc.org/content/285/15/11704.full.pdf+html
South, P. F., Fingerman, I. M., Mersman, D. P., Du, H. N., & Briggs, S. D. (2010). A conserved interaction between the SDI domain of Bre2 and the Dpy-3- Domain of Sdc1 is required for histone methylation and gene expression. J. Biol. Chem., 285(1), 595-607. Retrieved from http://www.jbc.org/content/285/1/595.full.pdf+html
Plazas-Mayorca, M. D., Zee, B. M., Young, N. L., Fingerman, I. M., LeRoy, G., Briggs, S. D., & Garcia, B. A. (2009). One-pot shotgun quantitative mass spectrometry characterization of histones. J. Proteome Res., 8(11), 5367-5374.
Mersman, D. P., Harmeyer, K. M., & Briggs, S. D. (2009). To be or not to be demethylated. Cell Cycle, 8, 2135-2137.
Mersman, D. P., Du, H. N., Fingerman, I. M., South, P. F., & Briggs, S. D. (2009). Polyubiquitination of the demethylase Jhd2 controls histone methylation and gene expression. Genes & Development, 23(8), 951-962.
Fingerman, I. M., Du, H., & Briggs, S. D. (2008). Controlling histone methylation via trans-histone pathways. Epigenetics, 3(5), 237-242.
Du, H., Fingerman, I., & Briggs, S. D. (2008). Histone H3 K36 methylation is mediated by a trans-histone methylation pathway involving an involing. Genes & Development, 22(20), 2786-2798.
Fingerman, I. M., Li, H. C., & Briggs, S. D. (2007). 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 and Development, 21, 2018-2029.