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

Wenyi Mi,Yongming Xue,Adam H Tencer,Qiong Tong,Xiaobing Shi,Wei Li,Tatiana G Kutateladze,Hong Wen,Jie Lyu,Danni Peng,Yi Zhang,Xiaolu Wang

doi:10.1038/s41467-018-06247-5

Abstract

Recognition of histones by epigenetic readers is a fundamental mechanism for the regulation of chromatin and transcription. Most reader modules target specific post-translational modifications on histones. Here, we report the identification of a 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 binding mechanism involving caging of the N-terminal Alanine 1 of histone H3 in an acidic cavity of the ZZ domain, indicating a specific recognition of H3 versus other histones. Depletion of ZZZ3 or disruption of the ZZ-H3 interaction dampens ATAC-dependent promoter histone H3K9 acetylation and target gene expression. Overall, our study identifies the ZZ domain of ZZZ3 as a histone H3 reader that is required for the ATAC complex-mediated maintenance of histone acetylation and gene activation.

Highlights

Recognition of histones by epigenetic readers is a fundamental mechanism for the regulation of chromatin and transcription
Our study identified the ZZ-type zinc finger (ZZ) domain of ZZZ3 as a versatile histone H3 reader that is required for the ATAC complex-mediated maintenance of histone acetylation and gene activation
Screening for novel readers by a homemade histone peptide array, we found that the ZZ of human ZZZ3 binds to the N-terminal tail of histone H3 in a methylationindependent manner (Fig. 1b)

Summary

Results

The ZZ domain is a histone H3-recognizing module. ZZZ3 contains two conserved domains, a putative DNA-binding Swi3Ada2-NCOR-TAFIIB (SANT) domain and a ZZ of unknown function (Fig. 1a). We found that 9 of the 16 ZZ domains could bind to histone H3 tail (Supplementary Fig. 1c–e), suggesting that H3 binding has evolved as a common function of ZZ domains within a subset of the protein family (Fig. 1h). To define the molecular mechanism by which ZZZ3 recognizes histone H3, we determined the solution structure of the ZZZ3 ZZ domain (aa 816–874) in complex with an unmodified histone H3 tail peptide (aa 1–12) by NMR spectroscopy. All the H3-binding ZZ domains contain an invariable aspartate (D848 in ZZZ3) along with an aspartate (D824 in ZZZ3) or asparagine (in p300 and CBP ZZs) (Supplementary Fig. 2g and the accompanied manuscript), suggesting that recognition of Ala of H3 through the acidic cage is likely a common mechanism of the ZZ readers. 10% input GST ZZZ3ZZ RBP2PHD1 10% input Beads H3 [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21] H3K4me H3K4me H3K4me H3K9me H3K9me H3K9me a ZZZ3 1 c

15 RBP2PHD1

Å F821

30 Flag-YEATS2

Methods