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Originally published In Press as doi:10.1074/mcp.M600007-MCP200 on April 20, 2006.
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Molecular & Cellular Proteomics 5:1314-1325, 2006.
© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

Quantitative Proteomic Analysis of Post-translational Modifications of Human Histones*

Hans Christian Beck{ddagger},§, Eva C. Nielsen§,¶, Rune Matthiesen§,¶,||, Lars H. Jensen{ddagger}{ddagger}, Maxwell Sehested**, Paul Finn§§, Morten Grauslund{ddagger}{ddagger}, Anne Maria Hansen{ddagger} and Ole Nørregaard Jensen,¶¶

From the {ddagger} Danish Technological Institute, Holbergsvej 10, DK-6000 Kolding, Denmark, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark, ** Department of Pathology, Diagnostic Centre, Copenhagen University Hospital, DK-2100 Copenhagen Ø, Denmark, {ddagger}{ddagger} TopoTarget A/S, Symbion Science Park, Fruebjergvej 3, DK-2100 Copenhagen, Denmark, and §§ TopoTarget UK Limited, 87A Milton Park, Abingdon, Oxon OX 14 4RY, United Kingdom

Histone proteins are subject to a range of post-transcriptional modifications in living cells. The combinatorial nature of these modifications constitutes the "histone code" that dictates chromatin structure and function during development, growth, differentiation, and homeostasis of cells. Deciphering of the histone code is hampered by the lack of analytical methods for monitoring the combinatorial complexity of reversible multisite modifications of histones, including acetylation and methylation. To address this problem, we used LC-MSMS technology and Virtual Expert Mass Spectrometrist software for qualitative and quantitative proteomic analysis of histones extracted from human small cell lung cancer cells. A total of 32 acetylations, methylations, and ubiquitinations were located in the human histones H2A, H2B, H3, and H4, including seven novel modifications. An LC-MSMS-based method was applied in a quantitative proteomic study of the dose-response effect of the histone deacetylase inhibitor (HDACi) PXD101 on histone acetylation in human cell cultures. Triplicate LC-MSMS runs at six different HDACi concentrations demonstrated that PXD101 affects acetylation of histones H2A, H2B, H3, and H4 in a site-specific and dose-dependent manner. This unbiased analysis revealed that a relative increase in acetylated peptide from the histone variants H2A, H2B, and H4 was accompanied by a relative decrease of dimethylated Lys57 from histone H2B. The dose-response results obtained by quantitative proteomics of histones from HDACi-treated cells were consistent with Western blot analysis of histone acetylation, cytotoxicity, and dose-dependent expression profiles of p21 and cyclin A2. This demonstrates that mass spectrometry-based quantitative proteomic analysis of post-translational modifications is a viable approach for functional analysis of candidate drugs, such as HDAC inhibitors.

¶¶ A Lundbeck Foundation Research Professor and the recipient of a Young Investigator Award from the Danish Natural Sciences Research Council. To whom correspondence should be addressed: Protein Research Group, Dept. of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. Tel.: 45-65502368; Fax: 45-65502467; E-mail: jenseno{at}bmb.sdu.dk


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