Histone H4 tail mediates allosteric regulation of nucleosome remodelling by linker DNA
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CitationHwang, William L., Sebastian Deindl, Bryan T. Harada, and Xiaowei Zhuang. 2014. “Histone H4 tail mediates allosteric regulation of nucleosome remodelling by linker DNA.” Nature 512 (7513): 213-217. doi:10.1038/nature13380. http://dx.doi.org/10.1038/nature13380.
AbstractISWI-family remodelling enzymes regulate access to genomic DNA by mobilizing nucleosomes1. These ATP-dependent chromatin remodellers promote heterochromatin formation and transcriptional silencing1 by generating regularly-spaced nucleosome arrays2-5. The nucleosome-spacing activity arises from regulation of nucleosome translocation by the length of extranucleosomal linker DNA6-10, but the underlying mechanism remains unclear. Here, we studied nucleosome remodelling by human ACF, an ISWI enzyme comprised of a catalytic subunit, Snf2h, and an accessory subunit, Acf12,11-13. We found that ACF senses linker DNA length through an interplay between its accessory and catalytic subunits mediated by the histone H4 tail of the nucleosome. Mutation of AutoN, an auto-inhibitory domain within Snf2h that bears sequence homology to the H4 tail14, abolished the linker-length sensitivity in remodelling. Addition of exogenous H4-tail peptide or deletion of the nucleosomal H4 tail also diminished the linker-length sensitivity. Moreover, the accessory subunit Acf1 bound the H4-tail peptide and DNA in a manner that depended on its N-terminal domain, and lengthening the linker DNA in the nucleosome reduced the proximity between Acf1 and the H4 tail. Deletion of the N-terminal portion of Acf1 (or its homologue in yeast) abolished linker-length sensitivity in nucleosome remodeling and led to severe growth defects in vivo. Taken together, our results suggest a mechanism for nucleosome spacing where linker DNA sensing by Acf1 is allosterically transmitted to Snf2h through the H4 tail of the nucleosome. For nucleosomes with short linker DNA, Acf1 preferentially binds to the H4 tail, allowing AutoN to inhibit the ATPase activity of Snf2h. As the linker DNA lengthens, Acf1 shifts its binding preference to the linker DNA, freeing the H4 tail to compete AutoN off the ATPase and thereby activating ACF.
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