Growing support for a histone acetylation code is based on the identification of relationships between specific histone modifications and distinct biological effects. This idea is supported by recent studies showing that bromodomain proteins interact with acetylated histones. Human Polybromo-1 is a subunit of Polybromo, BRG1-associated factors (PBAF) chromatin-remodeling complex required for kinetichore localization during mitosis. It is the hypothesis of this proposal that the Polybromo localizes PBAF at specific chromatin sites via the interaction of its six tandem bromodomains with acetylated histones. Preliminary results support this notion and show that single bromodomains interact with acetylated histone proteins in a site-specific manner. These exciting results are a major step toward understanding how proteins selectively interact with a variety of histone posttranslational modifications. The objective of these studies is to gain insights into Polybromo-nucleosome assembly events.
The specific aims are to: [1] identify the acetyl-histone binding sites targeted by single bromodomains, [2] examine the factors that confer acetyllysine recognition and site-specific binding, and [3] characterize the dependence of acetylation pattern on Polybromo-nucleosome assembly. Together, these three approaches will yield important insights into the acetylation dependence and site-specificity of bromodomain-histone interactions that are central to the localization and function of most known chromatin remodeling complexes. ? ? If a histone-based epigenetic code acts as a nuclear signaling network functioning through chromatin, then histone binding proteins must be key factors that translate the code. The results of this work will be a major step toward understanding how proteins selectively interact with histone posttranslational modifications. The approaches used here will provide a foundation for understanding the principles that define the acetylation dependence and site-specificity of bromodomain-histone interactions that are central to the localization and function of most known chromatin remodeling complexes. ? ? ?
| Thompson, Martin (2009) Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91:309-19 |
| Thompson, Martin (2009) Thermodynamic and kinetic analysis of bromodomain-histone interactions. Methods Enzymol 466:383-407 |
| Kupitz, Christopher; Chandrasekaran, Renu; Thompson, Martin (2008) Kinetic analysis of acetylation-dependent Pb1 bromodomain-histone interactions. Biophys Chem 136:7-12 |
| Thompson, Martin; Chandrasekaran, Renu (2008) Thermodynamic analysis of acetylation-dependent Pb1 bromodomain-histone H3 interactions. Anal Biochem 374:304-12 |
