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

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

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PALI1 promotes tumor growth through competitive recruitment of PRC2 to G9A-target chromatin for dual epigenetic silencing

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Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding

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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.     

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.     

组蛋白去甲基化酶KDM7家族在脑疾病中研究进展

组蛋白去甲基化酶KDM7家族包括KDM7A、KDM7B、KDM7C三种蛋白,主要通过去除与转录沉默相关的特定组蛋白赖氨酸甲基化修饰,进而对基因转录发挥调控作用。目前,对KDM7家族的研究主要集中于其在神经分化、肿瘤发生发展等过程中的作用,而对其在脑神经疾病中的作用却知之甚少。本文从该蛋白家族表观遗传调控机制、结构生物学及其在脑神经疾病中的作用等方面进行了综述,以期为研究其在脑神经疾病中的功能机制提供参考,为理解脑神经疾病分子病理机制以及探索基于该机制的有效治疗靶点带来新的启示。     

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.     

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.     

Dephosphorylation-induced EZH2 activation mediated RECK downregulation by ERK1/2 signaling

The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene, a widely known cancer inhibitor, could effectively suppress cancer metastasis and angiogenesis. Downregulation or loss of RECK expression frequently occurs during cancer progression. However, the mechanism underlying RECK dysregulation has not been fully elucidated. Herein, we reported for the first time that enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, could epigenetically attenuate RECK expression via catalyzing H3K27 trimethylation (H3K27me3) within the RECK promoter. Furthermore, we also proved, for the first time, the involvement of EZH2 in the inhibition of RECK by extracellular signal-related kinases (ERK)-1/2 signaling. Next, we revealed that the modulation of the enzymic activity of EZH2 resulting from posttranslational phosphorylation at the serine-21 site was responsible for the increased enrichment of H3K27me3 at the RECK promoter region by ERK1/2 signaling. Collectively, the results of our study shed more light on the mechanisms responsible for the dysregulation of RECK by the ERK1/2 pathway.     

CBX8 interacts with chromatin PTEN and is involved in regulating mitotic progression

ObjectivesBesides its role in regulating phosphatidylinositol‐3 kinase (PI3K) signalling in the cytosol, PTEN also has a nuclear function. In this study, we attempted to understand the mechanism of chromatin PTEN in suppressing chromosomal instability during cell division.Materials and methodsImmunocoprecipitation, ectopic expression, and deletional analyses were used to identify the physical interaction between Chromobox Homolog protein 8 (CBX8) and PTEN, as well as the functional domain(s) of PTEN mediating the interaction. Cell synchronization followed by immunoblotting was employed to study cell cycle regulation of CBX8 and the functional interaction between chromatin PTEN and CBX8. Small interfering RNAs (siRNAs) were used to study the role of PTEN and CBX8 in modulating histone epigenetic markers during the cell cycle.ResultsPolycomb group (PcG) proteins including CBXs function to repress gene expression in a wide range of organisms including mammals. We recently showed that PTEN interacted with CBX8, a component of Polycomb Repressing Complex 1 (PRC1), and that CBX8 co‐localized with PTEN in the nucleus. CBX8 levels were high, coinciding with its phosphorylation in mitosis. Phosphorylation of CBX8 was associated with monoubiquitinated PTEN and phosphorylated‐BubR1 on chromatin. Moreover, CBX8 played an important role in cell proliferation and mitotic progression. Significantly, downregulation of either PTEN or CBX8 induced H3K27Me3 epigenetic marker in mitotic cells.ConclusionCBX8 is a new component that physically interacts with chromatin PTEN, playing an important role in regulating mitotic progression.