Abstract
Knowledge of protein domains that function as the biological effectors for diverse post-translational modifications of histones is critical for understanding how nuclear and epigenetic programs are established. Indeed, mutations of chromatin effector domains found within several proteins are associated with multiple human pathologies, including cancer and immunodeficiency syndromes. To date, relatively few effector domains have been identified in comparison to the number of modifications present on histone and non-histone proteins. Here we describe the generation and application of human modified peptide microarrays as a platform for high-throughput discovery of chromatin effectors and for epitope-specificity analysis of antibodies commonly utilized in chromatin research. Screening with a library containing a majority of the Royal Family domains present in the human proteome led to the discovery of TDRD7, JMJ2C, and MPP8 as three new modified histone-binding proteins. Thus, we propose that peptide microarray methodologies are a powerful new tool for elucidating molecular interactions at chromatin.
Highlights
Chromatin structural dynamics regulate diverse cellular functions that influence survival, growth, and proliferation
Our results argue that MPP8CD, TDRD7TD, and JMJ2CTD represent three new domains with specific histone post-translational modification (PTM)-binding activity and that human epigenome peptide microarray platform (HEMP) technology can be used to identify and validate novel chromatin effectors
We demonstrated the utility of a modified histone peptide microarray to characterize methyl-lysine effector functions for the PHD fingers present within the yeast proteome [13]
Summary
Chromatin structural dynamics regulate diverse cellular functions that influence survival, growth, and proliferation. One of the major mechanisms for regulating chromatin structure involves the reversible covalent post-translational modification (PTM) of histone proteins by chemical moieties such as acetyl-, methyl- and phospho- groups. These chemical marks are proposed to constitute an epigenetic code that can be maintained in dividing cells and inherited across generations. Histone marks can act as ligands for modular protein domains found on chromatinregulatory proteins [3,4] In this context, the proteins and domains that recognize histone modifications, named ‘‘effectors’’ or ‘‘readers’’, are thought to define the functional consequences of many classes of modifications by transducing molecular events at chromatin into biological outcomes
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