ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes

Li, Na; Li, Yuanyuan; Lv, Jie; Zheng, Xiangdong; Wen, Hong; Shen, Hongjie; Zhu, Guangjing; Chen, Tsai-Yu; Dhar, S.; Kan, Pu Yeh; Wang, Zhibin; Shiekhattar, Ramin; Shi, Xiaobing; Lan, Fei; Chen, Kaifu; Li, Wei; Li, Haitao; Lee, Min Gyu

doi:10.1016/j.molcel.2016.06.035

Cited by 111 publications

(178 citation statements)

References 50 publications

(81 reference statements)

Supporting

Mentioning

158

Contrasting

Order By: Relevance

“…The top 500 genes with H3K4me3 peak broadness increase were also associated with enriched binding of transcriptional elongation mark H3K79me2 after C70 treatment (Figure S2F), implying that changes in H3K4me3 peak broadness may influence transcriptional elongation. At loci with the most significant increase in H3K4me3 peak broadness, such as in ZMYND8 encoding for a KDM5D co-repressor (Li et al, 2016), KDM5B and H3K4me3 peaks showed a clear overlap, suggesting that the decrease in KDM5B activity is directly linked to increased H3K4me3 broadness (Figure 2B). …”

Section: Resultsmentioning

confidence: 99%

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

et al. 2018

View full text Add to dashboard Cite

SUMMARY Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single cell RNA-seq, cellular barcoding, and mathematical modeling demonstrate that endocrine-resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor-resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.

show abstract

Section: Resultsmentioning

confidence: 99%

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

et al. 2018

View full text Add to dashboard Cite

show abstract

“…1A), and flavopiridol, a known CDK9 inhibitor, was one of the most efficacious compounds among a large panel of drugs tested on NMC cells and xenografts (35). Furthermore, our results suggest that the putative coregulatory module consisting of ZNF532 and ZMNYD8 should be considered for small-molecule targeting, as ZMNYD8 carries multiple chromatin modification binding domains that could be subject to inhibition (31).…”

Section: Discussionmentioning

confidence: 72%

“…Interestingly, it was previously reported that ZMYND8/ZNF532/ZNF592/ZNF687 interact with each other as a central hub in a large transcriptional network (26,30). ZMYND8 has several important chromatin-binding domains (bromodomain, PWWP, PHD finger, MYND), and can function as a combinatorial reader of histone modifications such as H3K4me1 and H3K14ac (31). Whether ZNF532 and ZMYND8 perform essential functions in NMC is still under investigation.…”

Section: Discussionmentioning

confidence: 99%

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

Alekseyenko

Walsh

Zee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

167

View full text Add to dashboard Cite

To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma (NMC), we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared with wild-type BRD4. Using cross-linking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 associated with BRD4-NUT in NMC patient cells but not detectable in 293T cells. EP300 and ZNF532 are both implicated in feed-forward regulatory loops leading to propagation of the oncogenic chromatin complex in BRD4-NUT patient cells. Adding key functional significance to our biochemical findings, we independently discovered a ZNF532-NUT translocation fusion in a newly diagnosed NMC patient. ChIP sequencing of the major players NUT, ZNF532, BRD4, EP300, and H3K27ac revealed the formation of ZNF532-NUT-associated hyperacetylated megadomains, distinctly localized but otherwise analogous to those found in BRD4-NUT patient cells. Our results support a model in which NMC is dependent on ectopic NUT-mediated interactions between EP300 and components of BRD4 regulatory complexes, leading to a cascade of misregulation.BioTAP-XL | hyperacetylation | ZNF532-NUT | topological domains | BRD4

show abstract

“…Recent work has suggested that another bromodomain protein, ZMYND8, is actively recruited to H4Ac at DSBs [172,183]. ZMYND8 is a transcriptional repressor containing a bromodomain, PWWP and PHD chromatin-binding domains [184]. These domains are tandemly arranged (PHD-BRD-PWWP) so that ZMYND8 functions as a combinatorial reader of multiple histone marks, including H3K14Ac/H3K4me [183,184].…”

Section: (C) H4ac and Bromodomainsmentioning

confidence: 99%

“…ZMYND8 is a transcriptional repressor containing a bromodomain, PWWP and PHD chromatin-binding domains [184]. These domains are tandemly arranged (PHD-BRD-PWWP) so that ZMYND8 functions as a combinatorial reader of multiple histone marks, including H3K14Ac/H3K4me [183,184]. ZMYND8 is recruited to DSBs through direct interaction with H4K8Ac/K12Ac, a process dependent on Tip60 (for H4Ac) and the bromodomain of ZMYND8 [172].…”

Section: (C) H4ac and Bromodomainsmentioning

confidence: 99%

The tale of a tail: histone H4 acetylation and the repair of DNA breaks

Dhar¹,

Gürsoy-Yüzügüllü²,

Parasuram³

et al. 2017

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

The ability of cells to detect and repair DNA double-strand breaks (DSBs) within the complex architecture of the genome requires co-ordination between the DNA repair machinery and chromatin remodelling complexes. This co-ordination is essential to process damaged chromatin and create open chromatin structures which are required for repair. Initially, there is a PARP-dependent recruitment of repressors, including HP1 and several H3K9 methyltransferases, and exchange of histone H2A.Z by the NuA4-Tip60 complex. This creates repressive chromatin at the DSB in which the tail of histone H4 is bound to the acidic patch on the nucleosome surface. These repressor complexes are then removed, allowing rapid acetylation of the H4 tail by Tip60. H4 acetylation blocks interaction between the H4 tail and the acidic patch on adjacent nucleosomes, decreasing inter-nucleosomal interactions and creating open chromatin. Further, the H4 tail is now free to recruit proteins such as 53BP1 to DSBs, a process modulated by H4 acetylation, and provides binding sites for bromodomain proteins, including ZMYND8 and BRD4, which are important for DSB repair. Here, we will discuss how the H4 tail functions as a dynamic hub that can be programmed through acetylation to alter chromatin packing and recruit repair proteins to the break site.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.

show abstract

ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes

Cited by 111 publications

References 50 publications

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

The tale of a tail: histone H4 acetylation and the repair of DNA breaks

Contact Info

Product

Resources

About