Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3

Finogenova, Ksenia; Bonnet, Jacques; Poepsel, Simon; Schäfer, Ingmar B.; Finkl, Katja; Schmid, Katharina; Litz, Claudia; Strauss, Mike; Benda, Christian; Müller, Jürg

doi:10.1101/2020.04.22.054684

Cited by 7 publications

(10 citation statements)

References 64 publications

(123 reference statements)

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“…EZHIP functions similarly to the oncogenic H3K27M mutant by binding to EZH2 and inhibiting its activity in trans (Hubner et al, 2019;Jain et al, 2019;Piunti et al, 2019). This mechanism seems similar to the trans-inhibition of EZH2 through PHF1 Tudor-H3K36me3 binding and recently described direct inhibitory effect of H3K36me3 on EZH2 catalytic activity (Finogenova et al, 2020;Jani et al, 2019). The molecular characterization of MBTD1-EZHIP will further reveal if parallels can be drawn with EPC1-PHF1.…”

Section: Discussionmentioning

confidence: 67%

“…We conclude that the mislocalization of H4 acetylation and the variant histone H2A.Z at the posterior HOXD gene locus in cells expressing EPC1-PHF1 leads to de-repression and productive transcription. Subsequent deposition of H3K36me3 – a histone mark linked to transcription elongation - blocks the spread of the repressive H3K27me3 mark, possibly in part through its recognition by the Tudor domain of PHF1 and direct effect on EZH2/PRC2 activity (Finogenova et al, 2020; Jani et al, 2019; Musselman et al, 2012; Schmitges et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…SUZ12 acts as a platform to assemble the non-canonical subunits of the PRC2 complex, and a recent study shows that mutations in SUZ12 can modulate PRC2.1 vs PRC2.2 formation (Youmans et al, 2021). Furthermore, recent structural data suggest that the JARID2-containing PRC2.2 complex can partially override H3K36me3-mediated inhibition of EZH2 catalytic activity (Kasinath et al, 2021), whereas the PRC2.1 complex is known to be catalytically inhibited by the presence of H3K36me3 (Finogenova et al, 2020; Musselman et al, 2012). We hypothesize that the loss of JARID2 in JAZF1-SUZ12 skews it to associate with the PRC2.1 complex, which is catalytically inhibited by the presence of the H3K36me3 modification.…”

Section: Resultsmentioning

confidence: 99%

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Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Sudarshan

Avvakumov

Lalonde

et al. 2021

Preprint

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Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with Endometrial Stromal Sarcomas (ESS) and Ossifying FibroMyxoid Tumors (OFMT) leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a co-activator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a mega-complex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome. These are linked to aberrant gene expression, in particular over an entire topologically-associated domain including part of the HOXD cluster. Furthermore, we show that JAZF1, implicated with PRC2 components in the most frequent translocations in ESS, is a potent transcription activator that physically associates with NuA4/TIP60. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas employ the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes leading to mislocalization of histone marks and aberrant polycomb target gene expression.

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Section: Discussionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Sudarshan

Avvakumov

Lalonde

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…An extended helical patch (3806-21, including M3812, L3814, and M3818) in MLL1 SET make hydrophobic interactions with the α2 (N73) and α3 (L85) helices and C-terminus (L108 and P109) of H2A (Figure 2C). There is also an electrostatic interaction between an arginine anchor (R3821) of SET-N and D72 of the α2 helix of H2A (Figure 2C), a common feature in many protein-NCP complexes (19-23). These interactions are specific for MLL1-NCP mode 1 .…”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, it is possible that linker DNA or adjacent nucleosomes are needed to further stabilize the MLL1 complex in vitro. Given that both the PRC2 and Rpd3S complexes require linker DNA for optimal chromatin binding and catalysis (19)(20)(21), it is possible that the nucleosome template assembled with linker DNA or an oligo-nucleosome array may reduce rotational dynamics of the MLL1 complex in vitro. Interestingly, the winged-helix motif in ASH2L is able to interact with DNA in a sequence-independent manner (22,23), which potentially allows for additional interactions with linker DNA.…”

Section: Discussionmentioning

confidence: 99%

MLL1 Methyltransferase Activity is Regulated by Distinct Nucleosome Binding Modes

Ayoub

Park

Y³

et al. 2021

Preprint

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Here we solve the single particle cryoEM structure for the MLL1 complex with nucleosome core particle (NCP) carrying histone H3 lysine 4 to methionine mutation. The MLL1 complex displays significant rotational dynamics on the NCP, a feature distinct from the yeast SET1 complex. We identified two major binding modes of the MLL1 complex on the NCP. Both binding modes anchor on the NCP through ASH2L, but they differ drastically with regard to where the MLL1 SET domain and RbBP5 bind. We show that one of the binding modes is catalytically inactive since disrupting interactions unique to this binding mode does not affect overall MLL1 activity in an NCP-specific manner. Interestingly, the inactive binding mode is in a configuration similar to that of the ySET1-NCP complex, which is intrinsically inactive on an unmodified NCP. The high rotational dynamics of the MLL1 complex as well as distinction between MLL and yeast SET1 complexes may reflect the necessity for loci-specific regulation of H3K4 methylation states in higher eukaryotes.

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The TAZ2 domain of CBP/p300 directs acetylation towards H3K27 within chromatin

Sheahan

Major

Webb

et al. 2020

Preprint

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The closely related acetyltransferases CBP and p300 are key regulators of gene expression in metazoans. CBP/p300 acetylate several specific lysine residues within nucleosomes, including histone H3 lysine 27 (H3K27), a hallmark of active enhancers and promoters. However, it has remained largely unclear how specificity of CBP/p300 towards H3K27 is achieved. Here we show that the TAZ2 domain of CBP is required for efficient acetylation of H3K27, while curbing activity towards other lysine residues within nucleosomes. We find that TAZ2 is a sequence-independent DNA binding module, promoting interaction between CBP and nucleosomes, thereby enhancing enzymatic activity and regulating substrate specificity of CBP. TAZ2 is further required to stabilize CBP binding to chromatin in mouse embryonic stem cells, facilitating specificity towards H3K27 and modulating gene expression. These findings reveal a crucial role of TAZ2 in regulating H3K27ac, while highlighting the importance of correct site-specific acetylation for proper regulation of gene expression.

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Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3

Abstract: One sentence summary: "Nucleosome binding by PRC2 threads H3K27 into its active site via an interaction network set in register by unmodified H3K36."

Cited by 7 publications

References 64 publications

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

MLL1 Methyltransferase Activity is Regulated by Distinct Nucleosome Binding Modes

The TAZ2 domain of CBP/p300 directs acetylation towards H3K27 within chromatin

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