EPOP Functionally Links Elongin and Polycomb in Pluripotent Stem Cells

Beringer, Malte; Pisano, Paola; Carlo, V. Di; Blanco, Enrique; Chammas, Paul; Vizán, Pedro; Gutiérrez, Arantxa; Aranda, Sergi; Payer, Bernhard; Wierer, Michael; Croce, Luciano Di

doi:10.1016/j.molcel.2016.10.018

Cited by 122 publications

(159 citation statements)

References 56 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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“…We confirmed co-immunoprecipitation of PRC2 subunits with EZHIP using mass spectrometry for protein identification ( Figure 1G). Recent studies have revealed that the core PRC2 subunits associate with mutually exclusive combinations of auxiliary subunits [28][29][30][31] . The PRC2.1 complex includes EPOP and the PCL proteins, while PRC2.2 associates with JARID2 and AEBP2 30,31 .…”

Section: Ezhip Forms a Stable Complex With Prc2 And Lowers H3k27me3 Imentioning

confidence: 99%

PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism

Jain

Truman

Lund

et al. 2019

Preprint

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Polycomb group (PcG) proteins are essential for development and are frequently misregulated in human cancers. Polycomb Repressive Complexes (PRC1, PRC2) function in a collaborative epigenetic cross-talk with H3K27me3 to initiate and maintain transcriptional silencing. Diffuse intrinsic pontine gliomas (DIPGs) have extremely low H3K27me3 levels mediated by H3 K27M oncohistone. Posterior fossa type A (PFA) ependymomas also exhibit very low H3K27 methylation but lack the K27M oncohistone. Instead, PFA tumors express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). We find that a highly conserved sequence within the C-terminus of EZHIP is necessary and sufficient to inhibit the catalytic activity of PRC2 in vitro and in vivo. Our biochemical experiments indicate that EZHIP directly interacts with the active site of the EZH2 subunit in a mechanism that is remarkably similar to the K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promote similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at the sites of PRC2 recruitment. Importantly, we find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a potential mechanism for loss of H3K27me3 spreading from CpG islands in vivo. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors-the K27M oncohistone and the EZHIP 'oncohistone-mimic'-that dysregulate gene silencing to promote tumorigenesis. Covalent modifications to both DNA and histone proteins allow chromatin to act as a dynamic information hub that integrates diverse biochemical stimuli to regulate genomic DNA access to the transcription machinery and ultimately establish and maintain cellular phenotypes. There is increasing appreciation that aberrant chromatin modifications are involved in the pathogenesis of cancer. Nowhere is this better supported than with the groundbreaking discoveries of highfrequency, somatic mutations in histones that are drivers of oncogenesis.

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“…In mESCs the Set2‐H3K36me3 enzyme leads to PRC2 mediated H3K27me1 deposition within highly transcribed genes (a modification coupled to RNA polymerase elongation) . Moreover, the Elongin BC And Polycomb Repressive Complex 2 Associated Protein (EPOP) regulate transcription at both H3K27me3 repressed and H3K4me3 active domains . EPOP knock‐out mESCs do not show any altered self renewal and morphology but carry an impaired distribution of H3K4me3, H2Bub and RNA polymerase II, due to EPOP interaction with the H2B deubiquitinase USP7 and impaired control of repressive PRC2‐Jarid2 complex …”

Section: Nuclear Prcs Reveal Unpredicted Interactors and Functionsmentioning

confidence: 99%

How Polycomb‐Mediated Cell Memory Deals With a Changing Environment

2018

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Cells and tissues are continuously exposed to a changing microenvironment, hence the necessity of a flexible modulation of gene expression that in complex organism have been achieved through specialized chromatin mechanisms. Chromatin-based cell memory enables cells to maintain their identity by fixing lineage specific transcriptional programs, ensuring their faithful transmission through cell division; in particular PcG-based memory system evolved to maintain the silenced state of developmental and cell cycle genes. In evolution the complexity of this system have increased, particularly in vertebrates, indicating combinatorial and dynamic properties of Polycomb proteins, in some cases even overflowing outside the cell nucleus. Therefore, their function may not be limited to the imposition of rigid states of genetic programs, but on the ability to recognize signals and allow plastic transcriptional changes in response to different stimuli. Here, we discuss the most novel PcG mediated memory functions in facing and responding to the challenges posed by a fluctuating environment.

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EPOP Functionally Links Elongin and Polycomb in Pluripotent Stem Cells

Cited by 122 publications

References 56 publications

Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription

Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription

PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism

How Polycomb‐Mediated Cell Memory Deals With a Changing Environment

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