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The primary objective of research in our lab is to dissect the fundamental molecular mechanisms governing the role of protein post-translational modifications in epigenetic and nuclear signaling pathways. We are currently interested in methylation of histone lysine residues, a modification system that has been well-established to regulate chromatin structure and function. Aberrant regulation of histone lysine methylation disrupts chromatin homeostasis and has been implicated in diverse human pathologies, including cancer, autoimmune and neurodegenerative disorders.

Our specific research goals are to (1) identify new mechanisms of chromatin regulation mediated by novel histone methylation events and (2) develop a comprehensive understanding of lysine methylation as a broad regulator of nuclear signaling pathways.

Lysine Methylation Signaling at Chromatin

The covalent post-translation modification (PTM) of histones, including methylation, acetylation, phosphorylation and ubiquitylation, is central to the organization of the genome and the establishment of functional domains within chromatin.  Histone modification is a highly dynamic process, orchestrated by an exquisitely regulated set of enzymes that catalyze the addition and removal of PTMs.  Specifically, methylation of lysine (K) residues on histones is performed by histone methyltransferases (KMTs), which add a mono-, di- or tri-methyl mark to the amino group of the lysine side chain, and these marks can be removed by lysine demethylases (KDMs).  Both classes of enzymes are highly conserved, with orthologs possessing similar catalytic and biological activities present in organisms ranging from yeast to humans.

lysine methylation reaction_cropThe addition of a methyl mark to histones serves as a molecular signal at chromatin to direct downstream functions.  This is mediated by the binding of chromatin effector proteins to methyl-lysine in a manner specified by the state (me1, me2 or me3) and chromatin context of the mark. Highly conserved methyl-lysine recognition domains within effector proteins drive this protein-protein interaction, and the binding of these molecules to methylated lysines within histones is known to govern such critical functions as gene expression, DNA replication, DNA damage repair and chromosome segregation.

KMT signaling_Cropped

Budding Yeast Lysine Methyltransferases

The model organism Saccharomyces cerevisiae has facilitated paradigm-setting investigations of the molecular mechanisms governing histone lysine methylation. The breadth of experimental tools available in yeast and the lower complexity of its epigenome has promoted extensive study of yeast KMTs and their cognate methyl marks. The most well-characterized are the highly conserved Set1, Set2 and Dot1, which catalyze H3K4me, H3K36me and H3K79me, respectively. Despite intense study, the catalytic activity and substrate specificity of several candidate KMTs remain undetermined in yeast, and the potential for these enzymes to target non-histone proteins is relatively unexplored. Our aim is to identify the histone and non-histone substrates and biological roles of these enzymes in yeast, which we expect to illuminate novel mechanisms of chromatin regulation and to uncover new interactions between chromatin modification and critical nuclear signaling pathways. We further expect this work to provide significant insight in to the contribution of lysine methylation to diverse pathological processes in humans.

Current Projects in the Lab

Functional characterization of novel sites of methylation on histone H4 at lysines 5, 8 and 12.

Determination of the regulatory mechanisms that guide histone lysine methyltransferase activity at chromatin. 

Elucidation of the biochemical and biological roles for uncharacterized lysine methyltransferases in budding yeast.