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Metabolically Derived Lysine Acylations and Neighboring Modifications Tune the Binding of the BET Bromodomains to Histone H4

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    Metabolically Derived Lysine Acylations and Neighboring Modifications Tune the Binding of the BET Bromodomains to Histone H4
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    † Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States
    ‡ Stem Cell Biology and Hematopoiesis Program, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin 53226, United States
    *E-mail: [email protected]
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    Biochemistry

    Cite this: Biochemistry 2017, 56, 41, 5485–5495
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    https://doi.org/10.1021/acs.biochem.7b00595
    Published September 25, 2017
    Copyright © 2017 American Chemical Society
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    Abstract

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    Recent proteomic studies discovered histone lysines are modified by acylations beyond acetylation. These acylations derive from acyl-CoA metabolites, potentially linking metabolism to transcription. Bromodomains bind lysine acylation on histones and other nuclear proteins to influence transcription. However, the extent bromodomains bind non-acetyl acylations is largely unknown. Also unclear are the effects of neighboring post-translational modifications, especially within heavily modified histone tails. Using peptide arrays, binding assays, sucrose gradients, and computational methods, we quantified 10 distinct acylations for binding to the bromodomain and extraterminal domain (BET) family. Four of these acylations (hydroxyisobutyrylation, malonylation, glutarylation, and homocitrullination) had never been tested for bromodomain binding. We found N-terminal BET bromodomains bound acetylated and propionylated peptides, consistent with previous studies. Interestingly, all other acylations inhibited binding of the BET bromodomains to peptides and nucleosomes. To understand how context tunes bromodomain binding, effects of neighboring methylation, phosphorylation, and acylation within histone H4 tails were determined. Serine 1 phosphorylation inhibited binding of the BRD4 N-terminal bromodomain to polyacetylated H4 tails by >5-fold, whereas methylation had no effect. Furthermore, binding of BRDT and BRD4 N-terminal bromodomains to H4K5acetyl was enhanced 1.4–9.5-fold by any neighboring acylation of lysine 8, indicating a secondary H4K8acyl binding site that is more permissive of non-acetyl acylations than previously appreciated. In contrast, C-terminal BET bromodomains exhibited 9.9–13.5-fold weaker binding for polyacylated than for monoacylated H4 tails, indicating the C-terminal bromodomains do not cooperatively bind multiple acylations. These results suggest acyl-CoA levels tune or block recruitment of the BET bromodomains to histones, linking metabolism to bromodomain-mediated transcription.

    Copyright © 2017 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biochem.7b00595.

    • Supporting methods, additional ITC data for histone H4 peptides containing propionyl, crotonyl, formyl, hydroxyisobutyryl, succinyl, and homocitrulline modifications (Supplementary Figure 1), and expected and observed masses of synthesized peptides (Supplementary Table 2) (PDF)

    • Quantitation of binding of BRD4-BD1 to the EpiTitan histone peptide array (Supplementary Table 1) (XLSX)

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    Cited By

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    This article is cited by 21 publications.

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    Biochemistry

    Cite this: Biochemistry 2017, 56, 41, 5485–5495
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.7b00595
    Published September 25, 2017
    Copyright © 2017 American Chemical Society
    Request reuse permissions

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