Epiproteomics: quantitative analysis of histone marks and codes by mass spectrometry

[Display omitted] •A useful reference for quantitative analysis of histone modifications.•Three general approaches to analyze histone modifications by mass spectrometry.•Analytical challenges of separation, instrumentation, and informatics for histones.•Strategies to implement LC–MS workflows for analysis of histone marks and codes. Histones are a group of proteins with a high number of post-translational modifications, including methylation, acetylation, phosphorylation, and monoubiquitination, which play critical roles in every chromatin-templated activity. The quantitative analysis of these modifications using mass spectrometry (MS) has seen significant improvements over the last decade. It is now possible to perform large-scale surveys of dozens of histone marks and hundreds of their combinations on global chromatin. Here, we review the development of three MS strategies for analyzing histone modifications that have come to be known as Bottom Up, Middle Down, and Top Down. We also discuss challenges and innovative solutions for characterizing and quantifying complicated isobaric species arising from multiple modifications on the same histone molecule.