Catherine Musselman Seminar

Event
Thursday, October 25, 2018 - 4:10pm to 5:00pm
Event Type: 

Department of Biochemistry - University of Iowa

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Host:  Vincenzo Venditti

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"Histone tail binding in the context of the nucleosome"

Histone tails harbor a plethora of post-translational modifications (PTMs) that direct the function of chromatin regulators.  Recognition of histone PTMs by these regulatory complexes is mediated through the action of reader sub-domains.  The interaction of reader domains with modified histone tails has been extensively studied using peptide fragments of the tails.  However, we have very little knowledge of how these domains associate with the full nucleosome.

We are using NMR spectroscopy and complimentary orthogonal techniques to investigate this, and have made two key discoveries. 1) The conformation of the histone tails in the context of the nucleosome has a dramatic effect on reader domain binding. 2) Many reader domains associate with both histones and DNA. Thus, in order to fully understand reader domain function it is critical to study them in the context of the nucleosome.  I will discuss results for two reader domains. The first is the  BPTF PHD finger, and its association with methylated lysine 4 on histone H3 (H3K4me3).  Here, we show that the conformation adopted by the histone H3 tails within the context of the nucleosome is inhibitory to binding of the BPTF PHD finger to H3K4me3, as compared to histone peptides.  We find that the H3 tails interact robustly but dynamically with nucleosomal DNA, and demonstrate that this inhibits PHD finger association. Modifications and mutations of the H3 tail outside the binding region increase the accessibility to PHD finger binding, indicating that PTM crosstalk can regulate reader domain binding by altering the nucleosome conformation.

The second reader domain I will discuss is the BRG1 bromodomain. We have found that this bromodomain can associate with both histone tails and DNA. I will discuss or studies into the mechanism of this novel DNA binding domain, and the interplay with histone association.