The ZZ-type zinc finger of ZZZ3 modulates the ATAC complex-mediated histone acetylation and gene activation

Recognition of post-translational modifications on histones by epigenetic readers is a fundamental mechanism for the regulation of chromatin and transcription. Compared to the large number of readers that recognize histone methylation, only a few acetyllysine readers have been identified, including bromodomain, YEATS, and double plant homeodomain zinc finger (DPF). Here, we report the identification of a novel reader of histone H3, the ZZ-type zinc finger (ZZ) domain of ZZZ3, a subunit of the Ada-Two-A Containing (ATAC) histone acetyltransferase complex. The solution NMR structure of the ZZ in complex with the H3 peptide reveals a unique histone-binding mechanism involving caging of the N-terminal Alanine 1 of histone H3 in an acidic cavity of the ZZ domain. Importantly, acetylation on Lysine 4 of H3 (H3K4ac) enhances the binding, and in cells, ZZZ3 colocalizes with H3K4ac across the genome. The recognition of histone acetylation by ZZ is essential for chromatin occupancy of ZZZ3 and functions of the ATAC complex. Depletion of ZZZ3 or disruption of the ZZ-H3 interaction dampens ATAC dependent promoter histone H3K9 acetylation and the expression of ribosomal protein encoding genes. Overall, our study identifies the ZZ domain of ZZZ3 as a novel epigenetic reader that links the GCN5/ATAC complex to histone acetylation. ZZZ3, H3K4ac, and H3K4me3 ChIP-seq in H1299 cells and H3K9ac ChIP-seq in control and ZZZ3 KD H1299 cells; ZZZ3 ChIP-seq in control, ZZZ3 KD and KD cells ectopically expressing shRNA-resistant WT or indicated mutants; Flag ChIP-seq in vector and cells overexpressing WT or indicated mutants. mRNA-seq of control and ZZZ3 KD in H1299 cells.