Abstract
Mass spectrometry (MS) is a powerful analytical method for the identification and quantification of co-existing post-translational modifications in histone proteins. One of the most important challenges in current chromatin biology is to characterize the relationships between co-existing histone marks, the order and hierarchy of their deposition, and their distinct biological functions. We developed the database CrossTalkDB to organize observed and reported co-existing histone marks as revealed by MS experiments of histone proteins and their derived peptides. Statistical assessment revealed sample-specific patterns for the co-frequency of histone post-translational modifications. We implemented a new method to identify positive and negative interplay between pairs of methylation and acetylation marks in proteins. Many of the detected features were conserved between different cell types or exist across species, thereby revealing general rules for cross-talk between histone marks. The observed features are in accordance with previously reported examples of cross-talk. We observed novel types of interplay among acetylated residues, revealing positive cross-talk between nearby acetylated sites but negative cross-talk for distant ones, and for discrete methylation states at Lys-9, Lys-27, and Lys-36 of histone H3, suggesting a more differentiated functional role of methylation beyond the general expectation of enhanced activity at higher methylation states.
Highlights
From the Department of Biochemistry and Molecular Biology University of Southern Denmark Campusvej 55 DK-5230 Odense M, Denmark
It has become evident that histone marks, i.e. co-existing PTMs, play a fundamental role in transcriptional and epigenetic regulation of the genome, and research is directed toward improving our understanding of inter- and intramolecular PTM cross-talk in histone proteins and other types of proteins
It was demonstrated that there is a correlation between methylation marks on H3K4 and acetylation marks on other lysine residues of H3 [4, 5]
Summary
Positive cross-talk leads to over-representation of PTM combinations, where one PTM triggers the addition of another PTM at a different residue either directly or indirectly through binding proteins. It was demonstrated that there is a correlation between methylation marks on H3K4 (lysine residue at position 4 of histone H3) and acetylation marks on other lysine residues of H3 [4, 5] Another example is the repressive H3K27me mark and the activating H3K4me mark, which form bivalent domains that maintain the repressive state of genes and that may be abrogated upon differentiation of the cell [6]. Negative cross-talk results from direct competition for a single residue, such as methylation and acetylation of the same lysine residue, or indirectly by changing the protein state preventing addition and recognition of the competing PTM [3]. The variety of possible effector molecules that read specific combination patterns is immense
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