The dynamic regulation of chromatin serves as an important mechanism for gene regulation. Many studies have demonstrated that posttranslational modification such as acetylation, phosphorylation, ubiquitination, and/or methylation of histones is a mechanism that regulates the chromatin environment and gene expression profiles. Many of these histone modifying activities, when disrupted (i.e., mutations, amplifications and chromosomal translocations), are associated with human cancers. Therefore, studying the machinery that mediates these modifications will provide us with a better understanding of how eukaryotic genomes are regulated and how mis-regulation of these modifying activities can lead to human diseases. The long-term objective of this proposal is to understand the biological role of Set1, the budding yeast histone H3 Lys4 methyltransferase, and its associated proteins in gene regulation. To achieve this goal we will use a combination of molecular, biochemical and genetic approaches to determine the importance of Set1-associated proteins in histone methylation, identify novel Set1-associated proteins, and characterize the functional domains of Set1 that regulate methyltransferase activity. Understanding the basic function of Set1 and Set1-associated proteins and how they mediate H3 Lys4 methylation will provide further mechanistic insight into how Set1 mediates gene regulation such as transcriptional activation, elongation and/or silencing. Finally, we predict that results from our studies will have wide implications since many SET domain-containing proteins exist in other organisms such as plants, insects and animals. Furthermore, several Set1 H3 Lys4 methyltransferase human homologues exist (e.g., MLL1, MLL2, and Set9) and have been associated with cancers. Therefore, understanding how Set1 functions in yeast may provide key insights into understanding how SET domain-containing methyltransferases lead to human diseases such as cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM074183-05S1
Application #
8003036
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Carter, Anthony D
Project Start
2010-01-20
Project End
2010-12-31
Budget Start
2010-01-20
Budget End
2010-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$130,840
Indirect Cost
Name
Purdue University
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
South, Paul F; Harmeyer, Kayla M; Serratore, Nina D et al. (2013) H3K4 methyltransferase Set1 is involved in maintenance of ergosterol homeostasis and resistance to Brefeldin A. Proc Natl Acad Sci U S A 110:E1016-25
Mersman, Douglas P; Du, Hai-Ning; Fingerman, Ian M et al. (2012) Charge-based interaction conserved within histone H3 lysine 4 (H3K4) methyltransferase complexes is needed for protein stability, histone methylation, and gene expression. J Biol Chem 287:2652-65
South, Paul F; Fingerman, Ian M; Mersman, Douglas P et al. (2010) A conserved interaction between the SDI domain of Bre2 and the Dpy-30 domain of Sdc1 is required for histone methylation and gene expression. J Biol Chem 285:595-607
Du, Hai-Ning; Briggs, Scott 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 285:11704-13
Mersman, Douglas P; Harmeyer, Kayla M; Briggs, Scott D (2009) To be or NOT to be demethylated. Cell Cycle 8:2135-7
Mersman, Douglas P; Du, Hai-Ning; Fingerman, Ian M et al. (2009) Polyubiquitination of the demethylase Jhd2 controls histone methylation and gene expression. Genes Dev 23:951-62
Plazas-Mayorca, Mariana D; Zee, Barry M; Young, Nicolas L et al. (2009) One-pot shotgun quantitative mass spectrometry characterization of histones. J Proteome Res 8:5367-74
Fingerman, Ian M; Du, Hai-Ning; Briggs, Scott D (2008) In Vitro Histone Methyltransferase Assay. CSH Protoc 3:nihpa83349
Du, Hai-Ning; Fingerman, Ian M; Briggs, Scott D (2008) Histone H3 K36 methylation is mediated by a trans-histone methylation pathway involving an interaction between Set2 and histone H4. Genes Dev 22:2786-98
Fingerman, Ian M; Du, Hai-Ning; Briggs, Scott D (2008) Controlling histone methylation via trans-histone pathways. Epigenetics 3:237-42

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