Metabolically-derived lysine acylations and neighboring modifications tune BET bromodomain binding to histone H4

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....

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Veröffentlicht in:Biochemistry (Easton) 2017-10, Vol.56 (41), p.5485-5495
Hauptverfasser: Olp, Michael D., Zhu, Nan, Smith, Brian C.
Format: Artikel
Sprache:eng
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Zusammenfassung: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 ten 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 BET bromodomain binding 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 BRD4 N -terminal bromodomain binding to polyacetylated H4 tails by >5-fold whereas methylation had no effect. Furthermore, BRDT and BRD4 N -terminal bromodomain binding to H4K5acetyl was enhanced 1.4- to 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- to 13.5-fold weaker binding for polyacylated compared to monoacylated H4 tails indicating the C -terminal bromodomains do not cooperatively bind multiple acylations. These results suggest acyl-CoA levels tune or block BET bromodomain recruitment to histones, linking metabolism to bromodomain-mediated transcription.
ISSN:0006-2960
1520-4995
DOI:10.1021/acs.biochem.7b00595