Recognition of a Mononucleosomal Histone Modification Pattern by BPTF via Multivalent Interactions

SummaryLittle is known about how combinations of histone marks are interpreted at the level of nucleosomes. The second PHD finger of human BPTF is known to specifically recognize histone H3 when methylated on lysine 4 (H3K4me2/3). Here, we examine how additional heterotypic modifications influence BPTF binding. Using peptide surrogates, three acetyllysine ligands are indentified for a PHD-adjacent bromodomain in BPTF via systematic screening and biophysical characterization. Although the bromodomain displays limited discrimination among the three possible acetyllysines at the peptide level, marked selectivity is observed for only one of these sites, H4K16ac, in combination with H3K4me3 at the mononucleosome level. In support, these two histone marks constitute a unique trans-histone modification pattern that unambiguously resides within a single nucleosomal unit in human cells, and this module colocalizes with these marks in the genome. Together, our data call attention to nucleosomal patterning of covalent marks in dictating critical chromatin associations.

Graphical AbstractFigure optionsDownload high-quality image (351 K)Download as PowerPoint slideHighlights
► The BPTF protein recognizes two different histone posttranslational modifications
► Binding both these marks on one nucleosome increases affinity and specificity
► BPTF colocalizes with bivalently marked nucleosomes in the nucleus
► The binding pattern suggests mononucleosomal bivalent marks confer specificity in vivo