Histone post-translational modifications play pivotal roles in eukaryotic gene expression through regulation of chromatin structure and/or recruitment of regulatory proteins to chromatin. To date, most studies have focused on modifications in unstructured histone N-terminal tail domains. In contrast, histone globular domains surrounded by DNA have been largely overlooked, despite the richness of their multiple modifications. To study the role of histone globular domain modifications in transcription, we have developed a biochemical screening system for homogenously modified nucleosome-interacting proteins. Here, we demonstrate that the human SWI/SNF complex directly interacts with acetylated lysine 56 on histone H3 (H3K56ac) and that this interaction enhances the nucleosome remodeling activity of the SWI/SNF complex. We further demonstrate that H3K56ac-SWI/SNF interaction enhances p53-dependent transcription from chromatin templates. Our study provides a molecular mechanism for gene expression regulated by interaction with a modified histone in the globular domain.