Roles of cofactors and chromatin accessibility in Hox protein target specificity
Roles of cofactors and chromatin accessibility in Hox protein target specificity
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DOI：
10.1186/s13072-015-0049-x
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发表时间：
2016-01-08
影响因子：
3.9
通讯作者：
White, Robert
中科院分区：
文献类型：
--
作者：
Beh, Ching Yew;El-Sharnouby, Sherif;White, Robert
背景：转录因子对特定靶基因的调节是我们理解发育和生理过程中基因网络控制的核心，但如何实现靶标特异性仍知之甚少。 Hox 转录因子家族很好地说明了这一点，因为它们有限的体外 DNA 结合特异性与其清晰的体内功能特异性形成鲜明对比。结果：在果蝇 Kc167 细胞中瞬时表达后，我们生成了三种 Hox 蛋白 Ubx、Abd-A 和 Abd-B 的全基因组结合谱，揭示了明确的靶标特异性和染色质可及性的显着影响。在缺乏 TALE 类同源域辅因子 Exd 和 Hth 的情况下，Ubx 和 Abd-A 结合在可及染色质中一组非常相似的靶位点，而 Abd-B 结合在另一组特定靶点上。 Hox 辅因子 Exd 和 Hth 的提供极大地改变了 Ubx 全基因组结合谱，使 Ubx 能够结合一组额外的新靶点。 Abd-B 特异性靶标和辅因子依赖性 Ubx 靶标均位于染色质中，在 Hox 蛋白/Hox 辅因子表达之前，DNase1 相对难以接近。结论：我们的实验证明染色质可及性在 Hox 蛋白结合中发挥着重要作用，并表明 Hox 蛋白与核小体的竞争在体内 Hox 蛋白靶标特异性中发挥着重要作用。
Background: The regulation of specific target genes by transcription factors is central to our understanding of gene network control in developmental and physiological processes yet how target specificity is achieved is still poorly understood. This is well illustrated by the Hox family of transcription factors as their limited in vitro DNA-binding specificity contrasts with their clear in vivo functional specificity.Results: We generated genome-wide binding profiles for three Hox proteins, Ubx, Abd-A and Abd-B, following transient expression in Drosophila Kc167 cells, revealing clear target specificity and a striking influence of chromatin accessibility. In the absence of the TALE class homeodomain cofactors Exd and Hth, Ubx and Abd-A bind at a very similar set of target sites in accessible chromatin, whereas Abd-B binds at an additional specific set of targets. Provision of Hox cofactors Exd and Hth considerably modifies the Ubx genome-wide binding profile enabling Ubx to bind at an additional novel set of targets. Both the Abd-B specific targets and the cofactor-dependent Ubx targets are in chromatin that is relatively DNase1 inaccessible prior to the expression of Hox proteins/Hox cofactors.Conclusions: Our experiments demonstrate a strong role for chromatin accessibility in Hox protein binding and suggest that Hox protein competition with nucleosomes has a major role in Hox protein target specificity in vivo.