The conformation of the histone H3 tail inhibits association of the BPTF PHD finger with the nucleosome

Abstract

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.

eLife digest

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.