Combinatorial histone modifications direct ATP-dependent chromatin remodeling by NURF to promoter proximal nucleosomes

NURF is a conserved ISWI-containing ATP-dependent chromatin remodeling complex that slides nucleosomes to control transcription and genome organization. Recognition of histone modifications (HPTMs) by reader domains has been proposed to focus remodeler action at discrete genome targets, either by controlling recruitment or through local allosteric regulation of core enzymatic activities. To distinguish mechanisms by which HPTMs influence NURF, we defined full HPTM-binding specificity of NURF by screening novel combinations of histone-reader interactions. We observe the NURF-selective subunit (BPTF/NURF301) recognises multiple H3 and H4 tail modifications via C-terminal PHD2 and bromodomains. Modified H3 recognition requires a new binding-pocket on PHD2 for H3K9AcS10p that cooperates with the known H3K4me3-binding hydrophobic-cage to enable high-affinity binding to triply-modified H3K4me3K9AcS10p. This combinatorial HPTM recognition discriminates and stabilises NURF recruitment to +1 nucleosomes of active genes, maintaining nucleosome position to control transcription. Our data establish direct, causal links between HPTM recognition, remodeler recruitment and consequent activity.