The conformation of the histone H3 tail inhibits association of the BPTF PHD finger with the nucleosome.
The conformation of the histone H3 tail inhibits association of the BPTF PHD finger with the nucleosome.
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DOI：
10.7554/elife.31481
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发表时间：
2018-04-12
期刊：
影响因子：
7.7
通讯作者：
Musselman CA
中科院分区：
文献类型：
--
作者：
Morrison EA;Bowerman S;Sylvers KL;Wereszczynski J;Musselman CA
组蛋白尾部含有大量的翻译后修饰，这些修饰指导染色质调节因子的功能，染色质调节因子通过效应域识别它们。效应域/组蛋白相互作用已被广泛研究，但主要是使用组蛋白尾部的肽片段。在这里，我们将这些研究扩展到核小体的背景下，发现组蛋白H3尾部所采用的构象对BPTF PHD指结合具有抑制作用。通过核磁共振波谱和分子动力学模拟，我们发现H3尾部与核小体DNA的相互作用是稳定而动态的，大大减少了PHD指关联。通过修饰或突变改变H3尾部的静电特性可以增加PHD指的可及性，这表明PTM串扰可以通过改变核小体构象来调节效应结构域结合。总之，我们的研究结果表明，核小体背景对组蛋白尾部的信号事件有巨大的影响，并强调了在核小体背景下研究组蛋白结合的重要性。人类基因组包含了构建人体所需的所有指令。然而，每个人类细胞并不能读取所有这些指令，这些指令以DNA编码基因的形式出现。相反，在每种类型的细胞中，不同的基因子集被打开，而其余的基因被关闭。人类细胞内的DNA被一种叫做组蛋白的蛋白质包裹，形成成千上万种叫做核小体的结构。如果编码基因的DNA含有很多核小体，那么DNA就不太容易接近，基因通常就会关闭；去除组蛋白或重新排列核小体可以激活基因。每个组蛋白都包含一个叫做尾巴的区域，因为它像猫的尾巴一样突出，可以用几十种不同的方式进行化学修饰。组蛋白修饰的特定组合被认为是核小体应该如何排列以使每个基因得到适当调节的信号。然而，目前还不清楚这些修饰组合是如何起作用的，因为从历史上看，在核小体的背景下研究尾巴是很困难的。相反，大多数研究都是观察从核小体上移除的尾部。现在，Morrison等人着手研究一种名为BPTF的蛋白质如何在人类核小体中识别组蛋白（称为H3K4me3）尾部的特定化学修饰。出乎意料的是，实验表明，BPTF与H3K4me3结合的组蛋白结合区域，当尾巴附着在核小体上时受到阻碍，而当它从核小体上移除时却没有受到阻碍。Morrison等人继续表明，这是因为组蛋白尾部被夹在核小体的其余部分上，不易接近。进一步的实验表明，额外的化学修饰使尾巴更容易接近，使组蛋白结合域更容易结合。总之，这些发现表明，组蛋白修饰的组合通过实际调节核小体本身，在核小体的背景下积极调节调节蛋白与H3K4me3的结合。已知组蛋白信号的破坏会导致许多疾病，包括癌症、自身免疫性疾病和神经系统疾病，这些发现可以指导进一步的研究，可能会导致新的治疗方法。然而，首先，需要做更多的工作来研究其他组蛋白修饰如何在核小体的背景下被识别，以及组蛋白信号的大量可能组合如何影响这一过程。
Histone tails harbor a plethora of post-translational modifications that direct the function of chromatin regulators, which recognize them through effector domains. Effector domain/histone interactions have been broadly studied, but largely using peptide fragments of histone tails. Here, we extend these studies into the nucleosome context and find that the conformation adopted by the histone H3 tails is inhibitory to BPTF PHD finger binding. Using NMR spectroscopy and MD simulations, we show that the H3 tails interact robustly but dynamically with nucleosomal DNA, substantially reducing PHD finger association. Altering the electrostatics of the H3 tail via modification or mutation increases accessibility to the PHD finger, indicating that PTM crosstalk can regulate effector domain binding by altering nucleosome conformation. Together, our results demonstrate that the nucleosome context has a dramatic impact on signaling events at the histone tails, and highlights the importance of studying histone binding in the context of the nucleosome. The human genome contains all the instructions needed to build the human body. However, each human cell does not read all of these instructions, which come in the form of genes encoded in the DNA. Instead, different subsets of genes are switched on in each type of cell, while the rest of the genes are switched off. DNA within human cells is wrapped around proteins called histones, to form hundreds of thousands of structures called nucleosomes. If the DNA that encodes a gene contains a lot of nucleosomes, the DNA is not very accessible and the gene will generally be off; removing the histones or rearranging the nucleosomes can turn the gene on. Each histone contains a region called a tail – because it protrudes like the tail of a cat – that can be chemically modified in dozens of different ways. Particular combinations of histone modifications are thought to signal how the nucleosomes should be arranged so that each gene is properly regulated. However, it is unclear how these combinations of modifications actually work because, historically, it has been difficult to study tails in the context of a nucleosome. Instead most studies had looked at tails that had been removed from the nucleosome. Now, Morrison et al. set out to investigate how one protein, called BPTF, recognizes a specific chemical modification on the tail of a histone, referred to as H3K4me3, in the context of a human nucleosome. Unexpectedly, the experiments showed that the histone-binding domain of BPTF, which binds to H3K4me3, was impeded when the tail was attached to the nucleosome but not when it was removed from the nucleosome. Morrison et al. went on to show that this was because the histone tail is tucked onto the rest of the nucleosome and not easily accessible. Further experiments revealed that additional chemical modifications made the tail more accessible, making it easier for the histone-binding domain to bind. Together these findings show that a combination of histone modifications acts to positively regulate the binding of a regulatory protein to H3K4me3 in the context of the nucleosome by actually regulating the nucleosome itself. The disruption of the histone signals is known to lead to a number of diseases, including cancer, autoimmune disease, and neurological disorders, and these findings could guide further research that may lead to new treatments. Yet first, much more work is needed to investigate how other histone modifications are recognized in the context of the nucleosome, and how the large number of possible combinations of histone signals affects this process.