Novel insights into the recognition of acetylated histone H4 tail by the TRIM24 PHD-Bromo module.
Biochem J
; 480(9): 629-647, 2023 05 15.
Article
em En
| MEDLINE
| ID: mdl-37075063
ABSTRACT
TRIM24 is a multi-functional chromatin reader, and it binds to the estrogen receptor to activate estrogen-dependent target genes associated with tumor development. TRIM24 is known to ubiquitinate p53 via an N-terminal RING domain and binds a specific combinatorial histone signature of H3K4me0/H3K23ac via its C-terminal plant homeodomain (PHD) and bromodomain (Bromo). Aberrant expression of TRIM24 positively correlates with H3K23ac levels, and high levels of both TRIM24 and H3K23ac predict poor survival of breast cancer patients. Little has been explored about the acetylated histone H4 (H4ac) signatures of TRIM24 and their biological functions. Herein, we report novel H4ac binding partners of TRIM24 and their localization in the genome. Isothermal titration calorimetry binding assay on the histone peptides revealed that the TRIM24 PHD-Bromo preferably binds to H4K5ac, H4K8ac, and H4K5acK8ac compared with other acetylated histone H4 ligands. Co-immunoprecipitation on the endogenous histones suggests that the recognition of H4ac by Bromo does not interfere with the recognition of H3K4me0 mark by the PHD domain of TRIM24. Consistent with this, TRIM24 PHD-Bromo exhibits minimal discrimination among H4ac binding partners at endogenous histone and nucleosome levels. Moreover, ChIP-seq analysis revealed that the H4K5ac and H4K8ac histone signatures strongly co-localize near the transcription start sites of different hub genes or TRIM24-targeted genes in breast cancer. In addition, the KEGG pathway analysis demonstrates that the TRIM24 and its H4ac targets are associated with several important biological pathways. Our findings describe that the H4ac recognition by TRIM24 PHD-Bromo enables access to the chromatin for specific transcriptional regulation.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Histonas
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Biochem J
Ano de publicação:
2023
Tipo de documento:
Article