5YE3

Crystal structure of the complex of di-acetylated histone H4 and 2A7D9 Fab fragment

5YE3 の概要

• エントリーDOI: 10.2210/pdb5ye3/pdb
• 分子名称: 2A7D9 VH CH1 chain, 2A7D9 L chain, di-acetylated histone H4, ... (4 entities in total)
• 機能のキーワード: antibody, histone, complex, nuclear protein
• 由来する生物種: Mus musculus; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 47331.73

構造登録者

Matsuda, T.,Ito, T.,Wakamori, M.,Umehara, T. (登録日: 2017-09-15, 公開日: 2018-08-22, 最終更新日: 2024-11-20)

主引用文献

Handoko, L.,Kaczkowski, B.,Hon, C.C.,Lizio, M.,Wakamori, M.,Matsuda, T.,Ito, T.,Jeyamohan, P.,Sato, Y.,Sakamoto, K.,Yokoyama, S.,Kimura, H.,Minoda, A.,Umehara, T.
JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states.
Epigenetics, 13:410-431, 2018

PubMed Abstract: The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

PubMed: 30080437
DOI: 10.1080/15592294.2018.1469891

実験手法

X-RAY DIFFRACTION (1.7 Å)