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Histone H4 tail mediates allosteric regulation of nucleosome remodelling by linker DNA

2014; Nature Portfolio; Volume: 512; Issue: 7513 Linguagem: Inglês

10.1038/nature13380

1476-4687

William L. Hwang, Sebastian Deindl, Bryan T. Harada, Xiaowei Zhuang,

Chromatin Remodeling and Cancer

A nucleosome-spacing mechanism for human ATP-dependent chromatin assembly and remodelling factor (ACF). Chromatin remodelling enzymes of the imitation switch (ISWI) family generate regular spacing between nucleosomes, which is critical for gene silencing and heterochromatin formation. Here, using single-molecule fluorescence resonance energy transfer in combination with various biochemical approaches, Xiaowei Zhuang and colleagues propose a nucleosome-spacing mechanism for the ISWI enzyme complex known as human ATP-dependent chromatin assembly and remodelling factor (ACF). DNA linker length is sensed by the ACF's accessory subunit (Acf1), and allosterically transmitted to the catalytic subunit (Snf2h) through the histone H4 tail of the nucleosome. The authors suggest that this mechanism may be generally applicable for ISWI family enzymes. Imitation switch (ISWI)-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 arrays2,3,4,5. The nucleosome-spacing activity arises from the dependence of nucleosome translocation on the length of extranucleosomal linker DNA6,7,8,9,10, but the underlying mechanism remains unclear. Here we study nucleosome remodelling by human ATP-dependent chromatin assembly and remodelling factor (ACF), an ISWI enzyme comprising a catalytic subunit, Snf2h, and an accessory subunit, Acf1 (refs 2, 11, 12, 13). We find 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, abolishes the linker-length sensitivity in remodelling. Addition of exogenous H4-tail peptide or deletion of the nucleosomal H4 tail also diminishes the linker-length sensitivity. Moreover, Acf1 binds both the H4-tail peptide and DNA in an amino (N)-terminal domain dependent manner, and in the ACF-bound nucleosome, lengthening the linker DNA reduces the Acf1-H4 tail proximity. Deletion of the N-terminal portion of Acf1 (or its homologue in yeast) abolishes linker-length sensitivity in remodelling and leads 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.