EPOP Interacts with Elongin BC and USP7 to Modulate the Chromatin Landscape

Liefke, Robert; Karwacki-Neisius, Violetta; Shi, Yang

doi:10.1016/j.molcel.2016.10.019

Cited by 96 publications

(133 citation statements)

References 45 publications

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“…A recent study (Beringer et al, 2016) showed that EloB and EloC indirectly bind to PRC2 by associating with the BC-box containing, PRC2-auxillary factor EPOP (Liefke and Shi, 2015; Liefke et al, 2016). However, EloA was not found to be part of this complex.…”

Section: Discussionmentioning

confidence: 99%

“…The complex is also part of a ubiquitin ligase complex along with Cullin5 and Rbx2 that drives degradation of stalled Pol II (Wilson et al, 2013). Two of the subunits of the Elongin complex have recently been linked to PRC2 via their interaction with the newly identified PRC2 interacting protein EPOP (Beringer et al, 2016; Liefke et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription

et al. 2017

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Summary Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non-histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of the PRC2 active site and used the resultant data to screen for uncharacterized potential targets. The RNA polymerase II (Pol II) transcription elongation factor, Elongin A (EloA), is methylated by PRC2 in vivo. Mutation of the methylated EloA residue decreased repression of a subset of PRC2 target genes as measured by both steady state and nascent RNA levels and perturbed embryonic stem cell differentiation. We propose that PRC2 modulates transcription of a subset of low expression target genes in part via methylation of EloA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription

et al. 2017

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“…ChIP experiments were performed by cross-linking ChIP as described 34 . In short, 100 million cells were crosslinked with 1% formaldehyde for 10 minutes.…”

Section: Methodsmentioning

confidence: 99%

“…Promoter reads were counted from -2000 to +2000 relative to the transcription start site and normalized to reads per million (rpm). Following public data sets were used: SUZ12 (GSM700554, GSM700553), PHF19 (GSM700556, GSM700555) 10 , MTF2 (GSM415050) 12 , MRE-Seq (GSM881347) 29 , H3K4me3 (GSM2027596) 34 . CpG island and promoter definitions were downloaded from the UCSC browser.…”

Section: Methodsmentioning

confidence: 99%

Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

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254

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The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression1,2 and plays essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like proteins (PCLs), including PHF1, MTF2 and PHF19, are PRC2 associated factors that form sub-complexes with PRC2 core components3, and have been proposed to modulate PRC2’s enzymatic activity or its recruitment to specific genomic loci4–13. Mammalian PRC2 binding sites are enriched in CG content, which correlate with CpG islands that display a low level of DNA methylation14. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood. In this study, we solved the crystal structures of the N-terminal domains of PHF1 and MTF2 with bound CpG-containing DNAs in the presence of H3K36me3-containing histone peptides. We found that the extended homologous (EH) regions of both proteins fold into a winged-helix structure, which specifically binds to the unmethylated CpG motif but in a manner completely different from the canonical winged-helix motif-DNA recognition. We further showed that the PCL EH domains are required for efficient recruitment of PRC2 to CpG island-containing promoters in mouse embryonic cells. Our research provides the first direct evidence demonstrating that PCLs are critical for PRC2 recruitment to CpG islands, thereby further clarifying their roles in transcriptional regulation in vivo.

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“…For example, H2Bub1 is usually believed to be an active marker for gene transcription and results in an open chromatin context to facilitate gene transcription [14][15][16][17]. In addition to the establishing enzymes, multiple deubiquitinases have also been identified, including USP7 [22][23][24][25], USP12 [26], USP22 [27], USP44 [28], USP46 [26], and USP49 [29]. In addition to the establishing enzymes, multiple deubiquitinases have also been identified, including USP7 [22][23][24][25], USP12 [26], USP22 [27], USP44 [28], USP46 [26], and USP49 [29].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Wang

Zhang³

et al. 2019

EMBO Reports

144

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Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non‐apoptotic cell death characterized by the iron‐dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin‐induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1‐mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.

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EPOP Interacts with Elongin BC and USP7 to Modulate the Chromatin Landscape

Cited by 96 publications

References 45 publications

Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription

Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription

Polycomb-like proteins link the PRC2 complex to CpG islands

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

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