Structure of the NuA4 acetyltransferase complex bound to the nucleosome

Qu, Keke; Chen, Kangjing; Wang, Hao; Li, Xueming; Chen, Zhucheng

doi:10.1038/s41586-022-05303-x

Cited by 29 publications

(14 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chemical trapping functionalities like norleucine for histone methyltransferases, methionine for LSD1 histone demethylase, and CoA for histone acetyltransferases have proven effective for the structural analysis of these enzymes. The use of thiourea as performed in this work rather than thioacetyl to trap Sirt6 nucleosome interactions may be of general advantage for the sirtuin family in analyzing nucleosome interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Though unexplored in this study, the proximity of the H2A C-tail to the Sirt6 active site suggests a possible H2A deacylase role that fits the function of Sirt6 in safeguarding genome integrity. 54 Chemical trapping functionalities like norleucine for histone methyltransferases, 55 methionine for LSD1 histone demethylase, 51 and CoA for histone acetyltransferases 56 have proven effective for the structural analysis of these enzymes. The use of thiourea as performed in this work rather than thioacetyl to trap Sirt6 nucleosome interactions may be of general advantage for the sirtuin family in analyzing nucleosome interactions.…”

Section: ■ Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation

et al. 2023

View full text Add to dashboard Cite

The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and gene expression. The sirtuins are a family of NAD-dependent HDAC enzymes, and one member, sirtuin 6 (Sirt6), influences DNA repair, transcription, and aging. Here, we demonstrate that Sirt6 is efficient at deacetylating several histone H3 acetylation sites, including its canonical site Lys9, in the context of nucleosomes but not free acetylated histone H3 protein substrates. By installing a chemical warhead at the Lys9 position of histone H3, we trap a catalytically poised Sirt6 in complex with a nucleosome and employ this in cryo-EM structural analysis. The structure of Sirt6 bound to a nucleosome reveals extensive interactions between distinct segments of Sirt6 and the H2A/H2B acidic patch and nucleosomal DNA, which accounts for the rapid deacetylation of nucleosomal H3 sites and the disfavoring of histone H2B acetylation sites. These findings provide a new framework for understanding how HDACs target and regulate chromatin.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Structural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation

et al. 2023

View full text Add to dashboard Cite

show abstract

“…7h). Notably, a recent study of the NuA4 acetyltransferase complex in yeast provides a structural basis for the dual function of H4 acetylation in regulating chromatin packaging and transcription activation 47 . Thus, we speculate that MOF-mediated H4K16ac is an intrinsic mechanism to link chromatin decompaction and transcription activation.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MOF-mediated Histone H4 Lysine 16 Acetylation Governs Mitochondrial and Ciliary Functions By Controlling Gene Promoters

Wang

Chandel

et al. 2022

Preprint

View full text Add to dashboard Cite

Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase (HAT) MOF, orchestrates critical functions in gene expression regulation and chromatin interaction. However, how does MOF and H4K16ac control cellular function and regulate mammalian tissue development remains unclear. Furthermore, whether the function of MOF is mediated by MSL or NSL, two distinct MOF-containing HAT complexes, have not been determined during mammalian development. Here we show that conditional deletion of Mof but not Kansl1, an essential component of the NSL complex, causes severe defects during murine skin development. In the absence of Mof and H4K16ac, basal epithelial progenitors of mammalian skin fail to establish the basement membrane and cell polarity, causing the failure of self-renewal. Furthermore, epidermal differentiation and hair growth are severely compromised, leading to barrier defects and perinatal lethality. Single-cell and bulk RNA-seq, in combination with MOF ChIP-seq, reveal that MOF regulated genes are highly enriched in mitochondria and cilia. Mechanistically, MOF coordinates with RFX2 transcription factor, which preferentially binds to gene promoters, to regulate ciliary and mitochondrial genes. Importantly, genetic deletion of Uqcrq, a nuclear-encoded, essential subunit for electron transport chain (ETC) Complex III, recapitulates the defects of epidermal differentiation and hair follicle growth observed in MOF cKO. Together, this study reveals the requirement of MOF-mediated epigenetic mechanism for mitochondria and cilia, and demonstrates the important function of the MOF/ETC axis for mammalian skin development.

show abstract

“…Currently, the Protein Data Bank (PDB [7]) includes more than 470 structures containing nucleosomes. These structures shed light on the details of interactions with regulatory proteins, changes caused by the introduction of PTMs, and mechanisms of chromatin compaction at the oligonucleosome level [5,[8][9][10]. However, all these structures were accumulated over the past 25 years, resulting in significant variability in chain naming and residue numbering.…”

Section: Introductionmentioning

confidence: 99%

NucleosomeDB - a database of 3D nucleosome structures and their complexes with comparative analysis toolkit

Армеев

Gribkova

Shaytan

2023

Preprint

View full text Add to dashboard Cite

Nucleosomes are basic building blocks of chromatin, comprising DNA wrapped around an octamer of eight histone proteins. They play key roles in DNA compaction, epigenetic mark up of the genome and actively participate in chromatin dynamics. X-ray and later cryo-EM studies have contributed greatly to our understanding of nucleosome structure, their interactions and dynamics. With over 470 nucleosome containing structures in the Protein Data Bank there is a wealth of information to be gleaned from these structures, especially through comparative analysis. However, due to the variability in their representation (chain naming, residue numbering, other artifacts), these structures cannot be systematically analyzed "as is". To address this issue, we developed a framework for analyzing and classifying nucleosome structures and their complexes, resulting in the creation of the NucleosomeDB database and the corresponding web-service. NucleosomeDB allows researchers to search, explore, and compare nucleosomes with each other, despite differences in composition and peculiarities of their representation. By utilizing the information contained within the NucleosomeDB, researchers can gain valuable insights into how nucleosomes interact with DNA and other proteins, assess the implications of mutations and protein binding on nucleosome structure. The detailed information contained within NucleosomeDB can contribute to a better understanding of the structure and function of nucleosomes, and ultimately, the functioning of chromatin and gene regulation. NucleosmeDB is freely available at https://nucldb.intbio.org.

show abstract

Structure of the NuA4 acetyltransferase complex bound to the nucleosome

Cited by 29 publications

References 59 publications

Structural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation

Structural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation

MOF-mediated Histone H4 Lysine 16 Acetylation Governs Mitochondrial and Ciliary Functions By Controlling Gene Promoters

NucleosomeDB - a database of 3D nucleosome structures and their complexes with comparative analysis toolkit

Contact Info

Product

Resources

About