Structural insights into the interactions of Polycomb Repressive Complex 2 with chromatin

2021 ◽  
Author(s):  
Akhil Gargey Iragavarapu ◽  
Liqi Yao ◽  
Vignesh Kasinath
Keyword(s):  
Target Genes ◽  
Histone H3 ◽  
Cell Type ◽  
Methyltransferase Activity ◽  
Post Translational Modifications ◽  
Polycomb Repressive Complex 2 ◽  
Polycomb Proteins ◽  
Polycomb Repressive Complexes ◽  
Structural Insights ◽  
Stimulation Of

Polycomb repressive complexes are a family of chromatin modifier enzymes which are critical for regulating gene expression and maintaining cell-type identity. The reversible chemical modifications of histone H3 and H2A by the Polycomb proteins are central to its ability to function as a gene silencer. PRC2 is both a reader and writer of the tri-methylation of histone H3 lysine 27 (H3K27me3) which serves as a marker for transcription repression, and heterochromatin boundaries. Over the last few years, several studies have provided key insights into the mechanisms regulating the recruitment and activation of PRC2 at Polycomb target genes. In this review, we highlight the recent structural studies which have elucidated the roles played by Polycomb cofactor proteins in mediating crosstalk between histone post-translational modifications and the recruitment of PRC2 and the stimulation of PRC2 methyltransferase activity.

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

2020 ◽  
Author(s):  
Vignesh Kasinath ◽  
Curtis Beck ◽  
Paul Sauer ◽  
Simon Poepsel ◽  
Jennifer Kosmatka ◽  
...  
Keyword(s):  
Zinc Fingers ◽  
Regulation Of Gene Expression ◽  
Inhibitory Effect ◽  
Histone H2a ◽  
Set Domain ◽  
Methyltransferase Activity ◽  
Post Translational Modifications ◽  
Nucleosomal Dna ◽  
Polycomb Repressive Complexes ◽  
Stimulation Of

ABSTRACTThe 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 H3K36-trimethylation 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.

scholarly journals Post-translational modifications of PRC2: signals directing its activity

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Yiqi Yang ◽  
Gang Li
Keyword(s):  
Catalytic Activity ◽  
Transcriptional Repression ◽  
Essential Role ◽  
Histone H3 ◽  
Post Translational Modifications ◽  
Polycomb Repressive Complex 2 ◽  
Cellular Identity ◽  
Organismal Development ◽  
Biochemical Signals ◽  
Insight Into

Abstract Polycomb repressive complex 2 (PRC2) is a chromatin-modifying enzyme that catalyses the methylation of histone H3 at lysine 27 (H3K27me1/2/3). This complex maintains gene transcriptional repression and plays an essential role in the maintenance of cellular identity as well as normal organismal development. The activity of PRC2, including its genomic targeting and catalytic activity, is controlled by various signals. Recent studies have revealed that these signals involve cis chromatin features, PRC2 facultative subunits and post-translational modifications (PTMs) of PRC2 subunits. Overall, these findings have provided insight into the biochemical signals directing PRC2 function, although many mysteries remain.

scholarly journals JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation

2021 ◽  
Author(s):  
Manuel Tavares ◽  
Garima Khandelwal ◽  
Joanne Mutter ◽  
Keijo Viiri ◽  
Manuel Beltran ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Target Genes ◽  
Histone H3 ◽  
Endometrial Stromal Sarcoma ◽  
Cell Types ◽  
Polycomb Repressive Complex 2 ◽  
Stromal Sarcoma ◽  
N Terminus ◽  
Undifferentiated Cells

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27me3) to maintain repression of genes specific for other cell types and is essential for cell differentiation. In endometrial stromal sarcoma, the PRC2 subunit SUZ12 is often fused with the NuA4/TIP60 subunit JAZF1. Here, we show that JAZF1-SUZ12 dysregulates PRC2 composition, recruitment, histone modification, gene expression and cell differentiation. The loss of the SUZ12 N-terminus in the fusion protein disrupted interaction with the PRC2 accessory factors JARID2, EPOP and PALI1 and prevented recruitment of PRC2 from RNA to chromatin. In undifferentiated cells, JAZF1-SUZ12 occupied PRC2 target genes but gained a JAZF1-like binding profile during cell differentiation. JAZF1-SUZ12 reduced H3K27me3 and increased H4Kac at PRC2 target genes, and this was associated with disruption in gene expression and cell differentiation programs. These results reveal the defects in chromatin regulation caused by JAZF1-SUZ12, which may underlie its role in oncogenesis.

scholarly journals EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Boheng Li ◽  
Wee-Joo Chng
Keyword(s):  
Gene Expression ◽  
Essential Role ◽  
Histone H3 ◽  
Epigenetic Silencing ◽  
Post Translational Modifications ◽  
Therapeutic Implications ◽  
Polycomb Repressive Complex 2 ◽  
Lymphoid Malignancies ◽  
Underlying Mechanisms

AbstractEZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which along with other PRC2 components mediates gene expression suppression via the methylation of Histone H3 at lysine 27. Recent studies have revealed a dichotomous role of EZH2 in physiology and in the pathogenesis of cancer. While it plays an essential role in the development of the lymphoid system, its deregulation, whether due to genetic or non-genetic causes, promotes B cell- and T cell-related lymphoma or leukemia. These findings triggered a boom in the development of therapeutic EZH2 inhibitors in recent years. Here, we discuss physiologic and pathogenic function of EZH2 in lymphoid context, various internal causes of EZH2 aberrance and how EZH2 modulates lymphomagenesis through epigenetic silencing, post-translational modifications (PTMs), orchestrating with surrounding tumor micro-environment and associating with RNA or viral partners. We also summarize different strategies to directly inhibit PRC2-EZH2 or to intervene EZH2 upstream signaling.

scholarly journals The deletion of the protein phosphatase 1 regulator NIPP1 in testis causes hyperphosphorylation and degradation of the histone methyltransferase EZH2

2018 ◽  
Vol 293 (47) ◽  
pp. 18031-18039 ◽  
Author(s):  
Mónica Ferreira ◽  
Iris Verbinnen ◽  
Margarida Fardilha ◽  
Aleyde Van Eynde ◽  
Mathieu Bollen
Keyword(s):  
Germ Cell ◽  
Protein Phosphatase ◽  
Target Genes ◽  
Histone H3 ◽  
Histone Methyltransferase ◽  
Protein Phosphatase 1 ◽  
Cyclin Dependent Kinase ◽  
Self Renewal ◽  
Polycomb Repressive Complex 2 ◽  
Epigenetic Regulators

Germ cell proliferation is epigenetically controlled, mainly through DNA methylation and histone modifications. However, the pivotal epigenetic regulators of germ cell self-renewal and differentiation in postnatal testis are still poorly defined. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, represses target genes through trimethylation of histone H3 at Lys-27 (H3K27me3), and interacts (in)directly with both protein phosphatase 1 (PP1) and nuclear inhibitor of PP1 (NIPP1). Here, we report that postnatal, testis-specific ablation of NIPP1 in mice results in loss of EZH2 and reduces H3K27me3 levels. Mechanistically, the NIPP1 deletion abrogated PP1-mediated EZH2 dephosphorylation at two cyclin-dependent kinase sites (Thr-345/487), thereby generating hyperphosphorylated EZH2, which is a substrate for proteolytic degradation. Accordingly, alanine mutation of these residues prolonged the half-life of EZH2 in male germ cells. Our study discloses a key role for the PP1:NIPP1 holoenzyme in stabilizing EZH2 and maintaining the H3K27me3 mark on genes that are important for germ cell development and spermatogenesis.

Fine‐tuning the stimulation of MLL1 methyltransferase activity by a histone H3‐based peptide mimetic

2010 ◽  
Vol 25 (3) ◽  
pp. 960-967 ◽  
Author(s):  
Vanja Avdic ◽  
Pamela Zhang ◽  
Sylvain Lanouette ◽  
Anastassia Voronova ◽  
Ilona Skerjanc ◽  
...  
Keyword(s):  
Histone H3 ◽  
Fine Tuning ◽  
Methyltransferase Activity ◽  
Peptide Mimetic ◽  
Stimulation Of

scholarly journals Polycomb group proteins in cancer: multifaceted functions and strategies for modulation

NAR Cancer ◽  
2021 ◽  
Vol 3 (4) ◽  
Author(s):  
Sijie Wang ◽  
Sandra C. Ordonez-Rubiano ◽  
Alisha Dhiman ◽  
Guanming Jiao ◽  
Brayden P Strohmier ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Complexes ◽  
Polycomb Group ◽  
Cancer Therapies ◽  
Transcriptional Repressors ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Methyltransferase Activity ◽  
Ubiquitin Ligase Activity ◽  
Polycomb Repressive Complexes

Abstract Polycomb repressive complexes (PRCs) are a heterogenous collection of dozens, if not hundreds, of protein complexes composed of various combinations of subunits. PRCs are transcriptional repressors important for cell-type specificity during development, and as such, are commonly mis-regulated in cancer. PRCs are broadly characterized as PRC1 with histone ubiquitin ligase activity, or PRC2 with histone methyltransferase activity; however, the mechanism by which individual PRCs, particularly the highly diverse set of PRC1s, alter gene expression has not always been clear. Here we review the current understanding of how PRCs act, both individually and together, to establish and maintain gene repression, the biochemical contribution of individual PRC subunits, the mis-regulation of PRC function in different cancers, and the current strategies for modulating PRC activity. Increased mechanistic understanding of PRC function, as well as cancer-specific roles for individual PRC subunits, will uncover better targets and strategies for cancer therapies.

scholarly journals ASCOM Controls Farnesoid X Receptor Transactivation through Its Associated Histone H3 Lysine 4 Methyltransferase Activity

2009 ◽  
Vol 23 (10) ◽  
pp. 1556-1562 ◽  
Author(s):  
Dae-Hwan Kim ◽  
Jeongkyung Lee ◽  
Bora Lee ◽  
Jae W. Lee
Keyword(s):  
Nuclear Receptors ◽  
Target Genes ◽  
Specific Interaction ◽  
Histone H3 ◽  
Farnesoid X Receptor ◽  
Mutant Form ◽  
Dependent Manner ◽  
Methyltransferase Activity ◽  
H3k4 Trimethylation ◽  
Lxxll Motif

Abstract Activating signal cointegrator-2 (ASC-2), a coactivator of multiple nuclear receptors and transcription factors, belongs to a steady-state complex named ASCOM (for ASC-2 complex), which contains histone H3 lysine 4 (H3K4) methyltransferase MLL3 or its paralog MLL4. ASC-2 binds to many nuclear receptors in a ligand-dependent manner through its two LxxLL motifs. Here we show that the first LxxLL motif of ASC-2 shows relatively weak but specific interaction with the nuclear receptor farnesoid X receptor (FXR) and that ASCOM plays crucial roles in FXR transactivation. Our results reveal that ASC-2, MLL3, and MLL4 are recruited to FXR target genes in a ligand-dependent manner. We further show that the recruitment of MLL3 requires ASC-2 and that FXR ligand induces not only expression of FXR-target genes but also their H3K4 trimethylation in a manner dependent on the presence of ASC-2, MLL3, and MLL4. In addition, MLL3 and MLL4 function redundantly with FXR transactivation. Correspondingly, expression of FXR target genes is partially impaired in mice expressing an enzymatically inactivated mutant form of MLL3, and these mice show disrupted bile acid homeostasis. Overall, these results suggest that ASCOM-MLL3 and ASCOM-MLL4 play redundant but essential roles in FXR transactivation via their H3K4 trimethylation activity.

scholarly journals Structural Insights into Stimulation of Ash1L's H3K36 Methyltransferase Activity through Mrg15 Binding

Structure ◽  
2019 ◽  
Vol 27 (5) ◽  
pp. 837-845.e3 ◽  
Author(s):  
Peini Hou ◽  
Chang Huang ◽  
Chao-Pei Liu ◽  
Na Yang ◽  
Tianshu Yu ◽  
...  
Keyword(s):  
Methyltransferase Activity ◽  
Structural Insights ◽  
Stimulation Of

scholarly journals PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma

2019 ◽  
Author(s):  
Haridha Shivram ◽  
Steven V. Le ◽  
Vishwanath R. Iyer
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Anaplastic Astrocytoma ◽  
Gene Expression Analysis ◽  
Histone H3 ◽  
Chromatin Binding ◽  
Chromosome 14 ◽  
Methyltransferase Activity ◽  
Polycomb Repressive Complex 2 ◽  
Interferon Stimulated Genes

AbstractPolycomb repressive complex 2 (PRC2) is a chromatin binding complex that represses gene expression by methylating histone H3 at K27 to establish repressed chromatin domains. PRC2 can either regulate genes directly through the methyltransferase activity of its component EZH2 or indirectly by regulating other gene regulators. Gene expression analysis of glioblastoma (GBM) cells lacking EZH2 showed that PRC2 regulates hundreds of interferon-stimulated genes (ISGs). We found that PRC2 directly represses several ISGs and also indirectly activates a distinct set of ISGs. Assessment of EZH2 binding proximal to miRNAs showed that PRC2 directly represses miRNAs encoded in the chromosome 14 imprinted DLK1-DIO3 locus. We found that repression of this locus by PRC2 occurs in immortalized GBM-derived cell lines as well as in primary bulk tumors from GBM and anaplastic astrocytoma patients. Through repression of these miRNAs and several other miRNAs, PRC2 activates a set of ISGs that are targeted by these miRNAs. This PRC2-miRNA-ISG network is likely to be important in regulating gene expression programs in GBM.

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