PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1

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Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors

Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the “tail” region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2^WT IC₅₀ = 22.0 nM). Compound 9b inhibited the proliferation of WSU-DLCL2 and SU-DHL-4 cell lines (IC₅₀ = 1.61 µM and 2.34 µM, respectively). The biological evaluation showed that 9b was a potent inhibitor for wild-type EZH2 and greatly reduced the overall levels of H3K27me3 in a concentration-dependent manner. Further study indicated that 9b could significantly induce apoptosis of SU-DHL-4 cells. These findings indicated that 9b would be an attractive lead compound for further optimization and evaluation.     

Broad Chromatin Domains: An Important Facet of Genome Regulation

Chromatin composition differs across the genome, with distinct compositions characterizing regions associated with different properties and functions. Whereas many histone modifications show local enrichment over genes or regulatory elements, marking can also span large genomic intervals defining broad chromatin domains. Here we highlight structural and functional features of chromatin domains marked by histone modifications, with a particular emphasis on the potential roles of H3K27 methylation domains in the organization and regulation of genome activity in metazoans.     

Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression

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Solution structure of the FCS zinc finger domain of the human polycomb group protein L(3)mbt‐like 2

Polycomb group proteins are epigenetic regulators that maintain patterns of gene expression over multiple rounds of cell division. Many of these proteins, including polyhomeotic and the MBT repeat containing proteins SCM and dSfmbt, contain an atypical C2C2 zinc finger with a characteristic phenylalanine–cysteine–serine sequence motif. The reoccurrence of this so‐called FCS zinc finger in a variety of polycomb group proteins suggests that it has an important regulatory function. We have determined the solution structure of the FCS zinc finger of the human dSfmbt homologue L(3)mbt‐like 2 (L3MBTL2). The structure consists of a β‐hairpin followed by an α‐helix. The zinc ligands are situated in the β‐hairpin and at the N‐terminus of the α‐helix an arrangement typical of the treble clef class of zinc fingers. The structure is consistent with the proposal that FCS zinc fingers bind to regulatory RNAs.     

BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

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Combinatorial Control of Recruitment of a Variant PRC1.6 Complex in Embryonic Stem Cells

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Drugging histone methyltransferases in cancer

Targeting chromatin-modifying enzymes is a promising strategy for cancer treatment. The antitumor effectivity of compounds inhibiting histone methyltransferases — mainly EZH2 — is currently being tested in phase I/II clinical trials, some of them showing positive results in hematological malignancies and solid tumors of specific mutational background. In this review, we aim at highlighting the recent advances in the field of histone methyltransferase inhibitors and describing the challenges that need to be addressed for their successful implementation in the clinics.     

The Polycomb group protein MEDEA controls cell proliferation and embryonic patterning in Arabidopsis

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Competition between PRC2.1 and 2.2 subcomplexes regulates PRC2 chromatin occupancy in human stem cells

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Hypoxia induced‐disruption of lncRNA TUG1/PRC2 interaction impairs human trophoblast invasion through epigenetically activating Nodal/ALK7 signalling

Inadequate trophoblastic invasion is considered as one of hallmarks of preeclampsia (PE), which is characterized by newly onset of hypertension (>140/90 mmHg) and proteinuria (>300 mg in a 24‐h urine) after 20 weeks of gestation. Accumulating evidence has indicated that long noncoding RNAs are aberrantly expressed in PE, whereas detailed mechanisms are unknown. In the present study, we showed that lncRNA Taurine upregulated 1 (TUG1) were downregulated in preeclamptic placenta and in HTR8/SVneo cells under hypoxic conditions, together with reduced enhancer of zeste homolog2 (EZH2) and embryonic ectoderm development (EED) expression, major components of polycomb repressive complex 2 (PRC2), as well as activation of Nodal/ALK7 signalling pathway. Mechanistically, we found that TUG1 bound to PRC2 (EZH2/EED) in HTR8/SVneo cells and weakened TUG1/PRC2 interplay was correlated with upregulation of Nodal expression via decreasing H3K27me3 mark at the promoter region of Nodal gene under hypoxic conditions. And activation of Nodal signalling prohibited trophoblast invasion via reducing MMP2 levels. Overexpression of TUG1 or EZH2 significantly attenuated hypoxia‐induced reduction of trophoblastic invasiveness via negative modulating Nodal/ALK7 signalling and rescuing expression of its downstream target MMP2. These investigations might provide some evidence for novel mechanisms responsible for inadequate trophoblastic invasion and might shed some light on identifying future therapeutic targets for PE.     

UV‐B radiation delays flowering time through changes in the PRC2 complex activity and miR156 levels in Arabidopsis thaliana

UV‐B is a high‐energy component of the solar radiation perceived by the plant and induces a number of modifications in plant growth and development, including changes in flowering time. However, the molecular mechanisms underlying these changes are largely unknown. In the present work, we demonstrate that Arabidopsis plants grown under white light supplemented with UV‐B show a delay in flowering time, and this developmental reprogramming is mediated by the UVR8 photoreceptor. Using a combination of gene expression analyses and UV‐B irradiation of different flowering mutants, we gained insight into the pathways involved in the observed flowering time delay in UV‐B‐exposed Arabidopsis plants. We provide evidence that UV‐B light downregulates the expression of MSI1 and CLF, two of the components of the polycomb repressive complex 2, which in consequence drives a decrease in H3K27me3 histone methylation of MIR156 and FLC genes. Modification in the expression of several flowering time genes as a consequence of the decrease in the polycomb repressive complex 2 activity was also determined. UV‐B exposure of flowering mutants supports the involvement of this complex in the observed delay in flowering time, mostly through the age pathway.