Comprehensive nucleosome interactome screen establishes fundamental principles of nucleosome binding

Abstract

<jats:title>Abstract</jats:title> <jats:p>Nuclear proteins bind chromatin to execute and regulate genome-templated processes. While studies of individual nucleosome interactions have suggested that an acidic patch on the nucleosome disk may be a common site for recruitment to chromatin, the pervasiveness of acidic patch binding and whether other nucleosome binding hot-spots exist remain unclear. Here, we use nucleosome affinity proteomics with a library of nucleosomes that disrupts all exposed histone surfaces to comprehensively assess how proteins recognize nucleosomes. We find that the acidic patch and two adjacent surfaces are the primary hot-spots for nucleosome disk interactions, whereas nearly half of the nucleosome disk participates only minimally in protein binding. Our screen defines nucleosome surface requirements of nearly 300 nucleosome interacting proteins implicated in diverse nuclear processes including transcription, DNA damage repair, cell cycle regulation and nuclear architecture. Building from our screen, we demonstrate that the Anaphase-Promoting Complex/Cyclosome directly engages the acidic patch, and we elucidate a redundant mechanism of acidic patch binding by nuclear pore protein ELYS. Overall, our interactome screen illuminates a highly competitive nucleosome binding hub and establishes universal principles of nucleosome recognition.</jats:p>

Binding of regulatory proteins to nucleosomes is modulated by dynamic histone tails

“…Indeed, it has been shown for PHD1/2 readers that they can bind up to ten-fold tighter to histone peptides compared to free nucleosomes [19]. A recent large-scale experimental study also demonstrates that many chromatin factors show enhanced binding to tailless nucleosomes compared to the full nucleosome, resulting from the increased solvent accessibility of DNA [57]. Our estimates of the binding free energy of the histone tail binding to DNA based on conformational sampling are on the order of several kcal/mol for H3 and H4 tails with the strongest binding exhibiting for H3 tail (Table SM4), which is consistent with previous experimental data on the tail-DNA binding free energies [58].…”

The Role of Nucleoporin Elys in Nuclear Pore Complex Assembly and Regulation of Genome Architecture

“…Furthermore, it was shown that the C-terminal domain of Elys, including the AT-hook, directly binds nucleosomes and H2A/H2B histone dimers [ 91 , 92 ]. This binding occurs with the acidic patch of H2A/H2B dimers [ 93 , 94 ].…”

Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome

“…Out data suggest that binding of the linker region through the arginine anchors to the H2A-H2B acidic pocket of the nucleosome stabilizes the activated conformation and/or prevents the enzyme from zipping back to the autoinhibited state, providing the mechanisms of ALC1 regulation by the nucleosomal epitopes. The residues neighboring the H2A-H2B acidic pocket are subjected to modifications, and the acidic pocket is believed to function as a tunable hub for many chromatin proteins 11,30 . Several chromatin remodelers, including Snf2 and ISWI, are also regulated by the H2A-H2B acidic pocket, although the mechanisms are not completely clear [31][32][33] .…”