Structural basis of nucleosome recognition and modification by MLL methyltransferases

Han, Xue; Yao, Tonghui; Cao, Mei; Zhu, Guanjun; Li, Yan; Yuan, Guiyong; Chen, Yong; Lei, Ming; Huang, Jing

doi:10.1038/s41586-019-1528-1

Cited by 139 publications

(208 citation statements)

References 43 publications

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“…As discussed further below, 190 this region of Cps50 is highly conserved and also mediates contacts between Cps50 191 and the core histone octamer, making this part of Cps50 a hotspot of COMPASS 192 interaction with the nucleosome. 193 194 Importantly, similar interactions between these COMPASS subunits (Cps60, Cps40 and 195 Cps50) and nucleosomal DNA have recently been observed in the human MLL1 196 complex (Xue et al, 2019) and the K. lactis COMPASS complex (Hsu et al, 2019), 197 indicating that these DNA interactions are critical for COMPASS function and are highly 198 conserved. 199…”

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confidence: 78%

“…At the tip of loop 2, 242 S289 forms a hydrogen bond with H3 K79. As compared to loop 1, loop 2 is not well 243 conserved ( Figure S4) and the contact it makes with H3K79 is not recapitulated in other 244 COMPASS-like complexes (Xue et al, 2019). Taken together, these results show that 245 the interaction between Cps50 and the nucleosome is conserved from yeast to humans 246 and is critical for COMPASS function in vivo.…”

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confidence: 93%

“…36 37 Structural studies of the core subcomplex (Hsu et al, 2018) and the H2B-ubiquitin-38 sensing subcomplex (Qu et al, 2018;Takahashi et al, 2012) have shown that 39 COMPASS adopts a Y-shaped, highly intertwined structure with the Set1 catalytic 40 domain at its core. Furthermore, a recent structure of the related human MLL1 core 41 complex bound to a ubiquitinated nucleosome revealed the underlying mechanisms of 42 nucleosome recognition by human COMPASS-like complexes (Xue et al, 2019). 43…”

Section: Introduction 1mentioning

confidence: 99%

“…Loop 1 is highly conserved ( Figure S4) and the residues that correspond to 233 V263 and I264 are always hydrophobic in character, indicating that that the interaction 234 we observe between Loop 1 and the histone octamer is structurally conserved among 235 Cps50 homologs. Indeed, the human MLL1 core complex subunit, Rbbp5, binds to the 236 histone octamer using a similar interface (Xue et al, 2019) and a recent preprint reports 237 that the K. lactis COMPASS complex Cps50/Swd1 subunit also utilizes the hydrophobic 238 cleft interface in a similar manner . 239…”

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confidence: 98%

“…Residues in the 261 Set1 RxR helix form several specific electrostatic interactions with acidic patch residues: 262 R908 contacts H2A residue E56 and H2B E113, R904 contacts H2A residue E61 and 263 R901 contacts H2A residues D90 and E92 (Figure 4d between Set1 R936 and H2A N68 on one side and Set1 R909 and H2B S112 on the 266 other side. Interestingly, the RxR motif is conserved in human Set1 homologs, but not in 282 the human paralogs MLL1-4 ( Figure S4) which have recently been shown not to bind 283 the nucleosome acidic patch (Xue et al, 2019). 284…”

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confidence: 99%

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Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome

Worden

Zhang

Wolberger

2019

Preprint

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Methylation of histone H3K4 is a hallmark of actively transcribed genes that depends on mono-ubiquitination of histone H2B (H2B-Ub). H3K4 methylation in yeast is catalyzed by Set1, the methyltransferase subunit of COMPASS. We report here the cryo-EM structure of a six-protein core COMPASS subcomplex, which can methylate H3K4 and be stimulated by H2B-Ub, bound to a ubiquitinated nucleosome. Our structure shows that COMPASS spans the face of the nucleosome, recognizing ubiquitin on one face of the nucleosome and methylating H3 on the opposing face. As compared to the structure of the isolated core complex, Set1 undergoes multiple structural rearrangements to cement interactions with the nucleosome and with ubiquitin. The critical Set1 RxR motif adopts a helix that mediates bridging contacts between the nucleosome, ubiquitin and COMPASS. The structure provides a framework for understanding mechanisms of trans-histone cross-talk and the dynamic role of H2B ubiquitination in stimulating histone methylation. (a) Cryo-EM structure of the COMPASS-nucleosome complex. The unsharpened EM density 71 showing two COMPASS molecules bound to the nucleosome is depicted as a semitransparent 72 surface. The sharpened EM density of the complex is depicted as an opaque surface and 73 colored according to the different subunits of the complex. (b) The model of the COMPASS-74 nucleosome complex is shown and colored as in panel a. The unstructured histone H3 tail 75 residues between the H3 exit point in the nucleosome and the Set1 active site are depicted as a 76 blue dashed line. (c) Large scale structural motions of COMPASS from the nucleosome-free 77 state to the nucleosome-bound state. Free COMPASS (PDB: 6BX3) is colored gray and 78 Nucleosome-bound COMPASS is colored according to panel b. The largest motion in the 79 structural transition at the end of Cps40 is shown as a black dashed arrow. (d) The COMPASS-80 nucleosome structure viewed from the dyad axis. The distances between the cis-H3 and trans-81 H3 subunits and the H3 residues in the Set1 active site are shown as dashed black lines. structure suggests that the previously observed conformational flexibility of COMPASS 129 is important for nucleosome recognition. 130 131The Set1 active site is oriented away from the nucleosome and contains density for the 132 SAM cofactor and the bound H3 tail (Figure 1d, Figure S3). The intervening sequence 133 of the H3 tail, from its exit point in the nucleosome (P38) to the first resolved residue in 134 the Set1 active site (T6), is not visible in the maps, suggesting that these residues are 135 highly mobile (Figures 1b, d). To determine which copy of histone H3 was connected to 136

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confidence: 78%

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confidence: 93%

Section: Introduction 1mentioning

confidence: 99%

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confidence: 98%

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confidence: 99%

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Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome

Worden

Zhang

Wolberger

2019

Preprint

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USP38 Couples Histone Ubiquitination and Methylation via KDM5B to Resolve Inflammation

Zhao

Liang

et al. 2020

Advanced Science

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Chromatin modifications, such as histone acetylation, ubiquitination, and methylation, play fundamental roles in maintaining chromatin architecture and regulating gene transcription. Although their crosstalk in chromatin remodeling has been gradually uncovered, the functional relationship between histone ubiquitination and methylation in regulating immunity and inflammation remains unclear. Here, it is reported that USP38 is a novel histone deubiquitinase that works together with the histone H3K4 modifier KDM5B to orchestrate inflammatory responses. USP38 specifically removes the monoubiquitin on H2B at lysine 120, which functions as a prerequisite for the subsequent recruitment of demethylase KDM5B to the promoters of proinflammatory cytokines Il6 and Il23a during LPS stimulation. KDM5B in turn inhibits the binding of NF-B transcription factors to the Il6 and Il23a promoters by reducing H3K4 trimethylation. Furthermore, USP38 can bind to KDM5B and prevent it from proteasomal degradation, which further enhances the function of KDM5B in the regulation of inflammation-related genes. Loss of Usp38 in mice markedly enhances susceptibility to endotoxin shock and acute colitis, and these mice display a more severe inflammatory phenotype compared to wild-type mice. The studies identify USP38-KDM5B as a distinct chromatin modification complex that restrains inflammatory responses through manipulating the crosstalk of histone ubiquitination and methylation.

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USP38 Couples Histone Ubiquitination and Methylation via KDM5B to Resolve Inflammation

Zhao¹,

Su²,

Liang³

et al. 2021

Advanced Science

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Figure S3. USP38 is dispensable for the TLR-stimulated signaling cascade. (A-B) Immunoblot analysis of phosphorylated (p-) and total proteins in whole-cell lysates of WT and Usp38-KO BMDMs (A) and BMDCs (B) that were stimulated with LPS for the indicated time points. (C) Immunoblot analysis of phosphorylated (p-) and total protein in whole-cell lysates of USP38-inducible THP1 cells with or without DOX that were stimulated with LPS for the indicated time points. (D) Immunoblot analysis of phosphorylated p65 in PBMCs silenced with control siRNA (siCtrl) or USP38-specific siRNA (siUSP38) under LPS treatment for the indicated time points. (E) Immunoblot analysis of USP38 in the chromatin-bound and unbound components of WT and Usp38-KO BMDMs under LPS treatment for the indicated time points. Data are representative of 3 independent biological experiments.

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Structural basis of nucleosome recognition and modification by MLL methyltransferases

Cited by 139 publications

References 43 publications

Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome

Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome

USP38 Couples Histone Ubiquitination and Methylation via KDM5B to Resolve Inflammation

USP38 Couples Histone Ubiquitination and Methylation via KDM5B to Resolve Inflammation

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