PRC1 Catalytic Activity Is Central to Polycomb System Function

Blackledge, Neil P.; Fursova, Nadezda A.; Kelley, Jessica R.; Huseyin, Miles K.; Feldmann, Angelika; Klose, Robert J.

doi:10.1016/j.molcel.2019.12.001

Cited by 211 publications

(230 citation statements)

References 125 publications

(196 reference statements)

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“…However, our measurements revealed that Polycomb bodies 192 accounted for just 1.3% of the total nuclear volume and that RING1B fluorescence signal 193 inside Polycomb bodies was only 1.3-fold more intense than the surrounding nucleus ( Figure 194 2J). This means that only 1.7% of total PRC1 signal originates from Polycomb bodies, 195 consistent with evidence from ChIP-seq experiments that PRC1 also binds more stably to 196 thousands of other smaller target sites in the genome (Blackledge et al, 2020;Endoh et al, 197 2012; Kloet et al, 2016;Morey et al, 2013). Therefore, PRC1 binds chromatin more stably at 198…”

Section: Only a Fraction Of Chromatin Bound Prc1 Displays Stable Bindsupporting

confidence: 52%

Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy

Huseyin

Klose

2020

Preprint

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8Polycomb repressive complex 1 (PRC1) is an essential chromatin-based repressor of gene 9 transcription. However, how PRC1 engages with chromatin to identify its target genes and 10 achieve gene repression remains poorly defined, representing a major hurdle to our 11 understanding of Polycomb system function. Here we use genome engineering and single 12 particle tracking to dissect how PRC1 binds to chromatin in live mouse embryonic stem cells. 13We reveal that PRC1 is highly dynamic, with only a small fraction stably interacting with 14 chromatin. By integrating subunit-specific dynamics, chromatin binding, and abundance 15 measurements, we discover that PRC1 exhibits surprisingly low occupancy at target sites. 16Furthermore, we employ perturbation approaches to uncover how specific components of 17

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Section: Only a Fraction Of Chromatin Bound Prc1 Displays Stable Bindsupporting

confidence: 52%

Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy

Huseyin

Klose

2020

Preprint

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“…PRC1 modulates both the structure and modification state of chromatin; functions grossly ascribed to canonical and non-canocial PRC1 respectively (Grau et al 2011;Isono et al 2013;Blackledge et al 2014;Rose et al 2016;Kundu et al 2017;Blackledge et al 2019;Plys et al 2019;Tatavosian et al 2019). What then is the relative contribution of these functions to gene represion?…”

Section: Prc1 Functionality and Gene Expressionmentioning

confidence: 99%

A Central Role for Canonical PRC1 in Shaping the 3D Nuclear Landscape

Boyle

Flyamer

Williamson

et al. 2019

Preprint

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Highlights:1. Loss of RING1B substantially disrupts nuclear architecture.2. PRC1 mediated looping can occur at a Mb scale and is independent of CTCF.3. Polycomb mediated looping is driven by canonical PRC1 complexes.4. Multimeric PRC1-mediated interactions occur in vitro and in vivo. Disruption of PRC1-mediated looping is independent of gene activation. AbstractPolycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus to form observable bodies; a conformation which is thought to contribute to gene silencing.However, how these interactions influence gross nuclear organisation and their relationship with transcription remains poorly understood. Here we examine the role of Polycomb Repressive Complex 1 (PRC1) in shaping 3D genome organization in mouse embryonic stem cells (mESCs). Using a combination of imaging and Hi-C analyses we show that PRC1-mediated long-range interactions are independent of CTCF and can bridge sites at a megabase scale. Impairment of PRC1 enzymatic activity does not directly disrupt these interactions. We demonstrate that PcG targets coalesce in vivo, and that developmentally induced expression of one of the target loci disrupts this spatial arrangement. Finally, we show that transcriptional activation and the loss of PRC1-mediated interactions are seperable events. These findings provide important insights into the function of PRC1, whilst highlighting the complexity of this regulatory system.

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“…Recent studies have suggested a highly regulated hierarchical recruitment model involving a complex crosstalk between the activities of the different PRC1 and PRC2 complexes in the establishment of polycomb heterochromatin domains (3,10). The loss of H2AK119ub1 on polycomb target genes has been observed to result in a corresponding reduction in H3K27me3 deposition, suggesting a strong connection between PRC1 and PRC2 catalytic activities (11,12). However, the specific role played by PRC1-mediated H2AK119ub1 in the recruitment of PRC2 has remained elusive, and there have been conflicting observations reporting both inhibition and activation of PRC2 by this histone mark (13,14).…”

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confidence: 99%

JARID2 and AEBP2 regulate PRC2 activity in the presence of H2A ubiquitination or other histone modifications

Kasinath

Beck

Sauer

et al. 2020

Preprint

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The Polycomb repressive complexes PRC1 and PRC2 functionally interact to coordinate cell type identity by the epigenetic regulation of gene expression. It has been proposed that PRC2 is recruited to genomic loci via the recognition of PRC1-mediated mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub1), but the mechanism of this process remains poorly understood. Here, we report the cryo-EM structure of human PRC2 with cofactors JARID2 and AEBP2 bound to a nucleosome substrate containing H2AK119ub1. We find that JARID2 and AEBP2 each interact with one of the two ubiquitin molecules in the nucleosome. A ubiquitin-interaction motif (UIM) in JARID2 is sandwiched between ubiquitin and the histone H2A-H2B acidic patch. Simultaneously, the tandem zinc-fingers of AEBP2 interact with the second ubiquitin and the histone H2A-H2B surface on the opposite side of the nucleosome. JARID2 plays a dual role in the H2AK119ub1 dependent stimulation of PRC2 through interactions with both EED via its K116 trimethylation and with the H2AK119-ubiquitin. AEBP2, on the other hand, appears to primarily serve as a scaffold contributing to the interaction between PRC2 and the H2AK119ub1 nucleosome. Our structure also provides a detailed visualization of the EZH2-nucleosome interface, revealing a segment of EZH2 (named "bridge helix") that is stabilized as it bridges the EZH2(SET) domain, the H3 tail and the nucleosomal DNA. In addition to the role played by AEBP2 and JARID2 in PRC2 regulation by H2AK119ub1 recognition, we also observe that the presence of these cofactors partially overcomes the inhibitory effect that H3K4-and H3K36trimethylation have on core PRC2. Together, our results reveal the central role played by cofactors JARID2 and AEBP2 in orchestrating the crosstalk between histone post-translational modifications and PRC2 methyltransferase activity.

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PRC1 Catalytic Activity Is Central to Polycomb System Function

Cited by 211 publications

References 125 publications

Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy

Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy

A Central Role for Canonical PRC1 in Shaping the 3D Nuclear Landscape

JARID2 and AEBP2 regulate PRC2 activity in the presence of H2A ubiquitination or other histone modifications

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