polycomb repressor complex

Sebastian C B Bremer, Lena-Christin Conradi, Nicolae-Catalin Mechie, Ahmad Amanzada, Eirini Mavropoulou, Julia Kitz, Michael Ghadimi, Volker Ellenrieder, Philipp Ströbel, Elisabeth Hessmann, Jochen Gaedcke, Hanibal Bohnenberger
BACKGROUND: Colorectal cancer (CRC) is the leading gastrointestinal malignancy. The development from premalignant intraepithelial lesions leading to invasive cancer is paradigmatic for the stepwise carcinogenesis of epithelial cancers, but the knowledge of the underlying mechanism of carcinogenesis and progression of CRC is still incomplete. The understanding of epigenetic mechanisms of carcinogenesis has led to new therapeutic approaches during the last years. Enhancer of zeste homolog 2 (EZH2) is one central epigenetic silencer of the polycomb repressor complex 2 (PRC2) that is already in clinical use as a novel drug target and is associated with poorer prognosis in several cancer entities...
November 6, 2019: Digestion
Xiaolin Zeng, Zheng Gao, Chuan Jiang, Yupeng Yang, Renyi Liu, Yuehui He
Polycomb repressive complex 2 (PRC2) catalyzes repressive histone 3 lysine-27 trimethylation (H3K27me3) to mediate genome-wide transcriptional repression in plants and animals. PRC2 controls various developmental processes in plants and plays a critical role in the developmental transition to flowering. FLOWERING LOCUS C (FLC), first identified in Arabidopsis (Arabidopsis thaliana), is a potent floral repressor in crucifers and some other plants that is subjected to complex regulation. Here, we show that HISTONE DEACETYLASE 9 (HDA9)-mediated H3K27 deacetylation is required for PRC2-mediated H3K27 trimethylation in Arabidopsis...
October 22, 2019: Plant Physiology
Hsiao-Yu Chiu, Hsu-Tung Lee, Kuo-Hsiung Lee, Yu Zhao, Chung Y Hsu, Woei-Cherng Shyu
AIMS: Investigations of the molecular mechanisms of hypoxia- and ischaemia-induced endogenous neural progenitor cell (NPC) proliferation have mainly focused on factors secreted in response to environmental cues. However, little is known about the intrinsic regulatory machinery underlying the self-renewing division of NPCs in the brain after stroke. METHODS AND RESULTS: Polycomb repressor complex 1-chromobox7 (CBX7) has emerged as a key regulator in several cellular processes including stem cell self-renewal and cancer cell proliferation...
October 19, 2019: Neuropathology and Applied Neurobiology
Delfina A Ré, Damian A Cambiagno, Agustin L Arce, Ariel H Tomassi, Marisol Giustozzi, Paula Casati, Federico D Ariel, Pablo A Manavella
CURLY LEAF (CLF) encodes the methyl-transferase sub-unit of the Polycomb Repressor Complex 2 (PRC2), which regulates the expression of target genes through H3K27 tri-methylation. We isolated a new CLF mutant allele (clf-78) using a genetic screening designed to identify micro RNAs (miRNA) deficient mutants. CLF mutant plants showed impaired miRNA activity caused by increased AGO1 ubiquitination and enhanced degradation in specific tissues. Such CLF-mediated AGO1 regulation was evidenced when plants were exposed to UV radiation, causing increased susceptibility of clf mutants to some UV-induced responses...
October 10, 2019: Molecular Plant
Alison Hirukawa, Salendra Singh, Jarey Wang, Jonathan P Rennhack, Matthew Swiatnicki, Virginie Sanguin-Gendreau, Dongmei Zuo, Kamilia Daldoul, Cynthia Lavoie, Morag Park, Eran R Andrechek, Thomas F Westbrook, Lyndsay N Harris, Vinay Varadan, Harvey W Smith, William J Muller
Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me3 , a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2)...
October 8, 2019: Cell Reports
Bin Li, Yuyuan Chen, Fei Wang, Jun Guo, Wen Fu, Min Li, Qichang Zheng, Yong Liu, Lingling Fan, Lei Li, Chuanrui Xu
Bmi1 is overexpressed in one-third of hepatocellular carcinoma (HCC) patients and acts as an oncogene in hepatocarcinogenesis. However, the underlying mechanism is unclear. The role of TGFβ signalling in HCC is not well defined as well. Here, we report that TGFβ2 is a target of Bmi1 in HCC and has a tumour-suppressing role. In Bmi1-knockout mouse livers and HCC cell lines, TGFβ2/SMAD cascade proteins were upregulated. TGFβ2 expression was inversely correlated with Bmi1 expression in human and mouse HCC tissues...
October 7, 2019: Oncogene
F-P Li, D-Q Ling, L-Y Gao
OBJECTIVE: Recent studies highlighted long noncoding RNAs (lncRNAs) have been implicated in many biological processes and diseases. However, atherosclerosis is a major risk factor for cardiovascular disease, but the detailed mechanism of atherosclerosis progression remained unclear. In this study, we mainly focused on the role of lncRNA Chaer in atherosclerosis. PATIENTS AND METHODS: RT-PCR was used to detect the expression of lncRNA Chaer in atherosclerosis patients and animal model...
September 2019: European Review for Medical and Pharmacological Sciences
Panagiotis Papoutsoglou, Yutaro Tsubakihara, Laia Caja, Anita Morén, Paris Pallis, Adam Ameur, Carl-Henrik Heldin, Aristidis Moustakas
Molecular processes involving lncRNAs regulate cell function. By applying transcriptomics, we identify lncRNAs whose expression is regulated by transforming growth factor β (TGF-β). Upon silencing individual lncRNAs, we identify several that regulate TGF-β signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-β through Smad and protein kinase pathways and resides in the nucleus. Depleting TGFB2-AS1 enhances TGF-β/Smad-mediated transcription and expression of hallmark TGF-β-target genes...
September 17, 2019: Cell Reports
Megan L Linscott, Wilson C J Chung
Fibroblast growth factor 8 (FGF8) is a potent morphogen that regulates the ontogenesis of gonadotropin-releasing hormone (GnRH) neurons, which control the hypothalamus-pituitary-gonadal (HPG) axis, and therefore reproductive success. Indeed, FGF8 and FGFR1 deficiency severely compromises vertebrate reproduction in mice and humans and is associated with Kallmann Syndrome (KS), a congenital disease characterized by hypogonadotropic hypogonadism associated with anosmia. Our laboratory demonstrated that FGF8 signaling through FGFR1, both of which are KS-related genes, is necessary for proper GnRH neuron development in mice and humans...
2019: PloS One
Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I Scher, Ouathek Ouerfelli, Filippo G Giancotti
The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in double-negative prostate cancer (DNPC). In vivo genetic screening identifies CCL2 as the top prometastatic gene induced by PRC1. CCL2 governs self-renewal and induces the recruitment of M2-like tumor-associated macrophages and regulatory T cells, thus coordinating metastasis initiation with immune suppression and neoangiogenesis...
August 12, 2019: Cancer Cell
Barbara Storti, Simone Civita, Paolo Faraci, Giorgia Maroni, Indira Krishnan, Elena Levantini, Ranieri Bizzarri
Several in vitro experiments have highlighted that the Polycomb group protein BMI1 plays a pivotal role in determining the biological functions of the Polycomb Repressor Complex 1 (PRC1), including its E3-ligase activity towards the Lys119 of histone H2A to yield ubiquitinated uH2A. The role of BMI1 in the epigenetic activity of PRC1 is particularly relevant in several cancers, particularly Non-Small Cell Lung Cancer (NSCLC). In this study, using indirect immunofluorescence protocols implemented on a confocal microscopy apparatus, we investigated the relationship between BMI1 and uH2A at different resolutions, in cultured (A549) and clinical NSCLC tissues, at the single cell level...
July 11, 2019: Biophysical Chemistry
Simona Dedoni, Luisa Marras, Maria C Olianas, Angela Ingianni, Pier Luigi Onali
Valproic acid (VPA) has been shown to regulate the levels of brain-derived neurotrophic factor (BDNF) but it is not known whether this drug can affect the neuronal responses to BDNF. In the present study we show that in retinoic acid-differentiated SH-SY5Y human neuroblastoma cells prolonged exposure to VPA reduces the expression of the BDNF receptor TrkB at the protein and mRNA levels, and inhibits the intracellular signalling, neurotrophic activity and pro-survival function of BDNF. VPA down-regulates TrkB and curtails BDNF-induced signalling also in differentiated Kelly and LAN-1 neuroblastoma cells and primary mouse cortical neurons...
July 15, 2019: Journal of Pharmacology and Experimental Therapeutics
Harvey W Smith, Alison Hirukawa, Virginie Sanguin-Gendreau, Ipshita Nandi, Catherine R Dufour, Dongmei Zuo, Kristofferson Tandoc, Matthew Leibovitch, Salendra Singh, Jonathan P Rennhack, Matthew Swiatnicki, Cynthia Lavoie, Vasilios Papavasiliou, Carolin Temps, Neil O Carragher, Asier Unciti-Broceta, Paul Savage, Mark Basik, Vincent van Hoef, Ola Larsson, Caroline L Cooper, Ana Cristina Vargas Calderon, Jane Beith, Ewan Millar, Christina Selinger, Vincent Giguère, Morag Park, Lyndsay N Harris, Vinay Varadan, Eran R Andrechek, Sandra A O'Toole, Ivan Topisirovic, William J Muller
Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation...
July 1, 2019: Nature Communications
Jing Liang, Qi Li, Wenbin Cai, Xuejiao Zhang, Bing Yang, Xin Li, Shuai Jiang, Shanshan Tian, Kai Zhang, Hao Song, Ding Ai, Xu Zhang, Chunjiong Wang, Yi Zhu
BACKGROUND AND PURPOSE: Promoted proliferation and migration of vascular smooth muscle cells (VSMCs) after arterial injury contributes greatly to the pathogenesis of neointimal hyperplasia. As a major component of epigenetics, histone methylation plays an important role in several cardiovascular diseases. However, its role in restenosis is still unclear. EXPERIMENTAL APPROACH: Human aortic VSMCs were challenged with platelet-derived growth factor-BB (PDGF-BB) and total histones were extracted and analyzed by HPLC/MS...
June 4, 2019: British Journal of Pharmacology
S Alexandra Garcia-Moreno, Yi-Tzu Lin, Christopher R Futtner, Isabella M Salamone, Blanche Capel, Danielle M Maatouk
XX and XY fetal gonads are initially bipotential, poised between the ovary and testis fate. Multiple lines of evidence suggest that commitment to testis fate requires the repression of genes associated with ovary fate. It was previously shown that loss of CBX2, the subunit of the Polycomb Repressive Complex 1 (PRC1) that binds H3K27me3 and mediates silencing, leads to ovary development in XY mice and humans. While it had been proposed that CBX2 is an activator of the testis-determining gene Sry, we investigated the alternative possibility that CBX2 has a direct role as a repressor of the antagonistic ovary-promoting pathway...
May 22, 2019: PLoS Genetics
L Telley, G Agirman, J Prados, N Amberg, S Fièvre, P Oberst, G Bartolini, I Vitali, C Cadilhac, S Hippenmeyer, L Nguyen, A Dayer, D Jabaudon
During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage of the molecular identities of successive generations of apical progenitors (APs) and their daughter neurons in mouse embryos. We identified a core set of evolutionarily conserved, temporally patterned genes that drive APs from internally driven to more exteroceptive states...
May 10, 2019: Science
Jung-Won Lee, Da-Mi Kim, Ju-Won Jang, Tae-Geun Park, Soo-Hyun Song, You-Soub Lee, Xin-Zi Chi, Il Yeong Park, Jin-Won Hyun, Yoshiaki Ito, Suk-Chul Bae
The cellular decision regarding whether to undergo proliferation or death is made at the restriction (R)-point, which is disrupted in nearly all tumors. The identity of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in cell biology. We found that early after mitogenic stimulation, RUNX3 binds to its target loci, where it opens chromatin structure by sequential recruitment of Trithorax group proteins and cell-cycle regulators to drive cells to the R-point. Soon after, RUNX3 closes these loci by recruiting Polycomb repressor complexes, causing the cell to pass through the R-point toward S phase...
April 23, 2019: Nature Communications
Mark E Pepin, Hayden H Bickerton, Maigen Bethea, Chad S Hunter, Adam R Wende, Ronadip R Banerjee
Pancreatic β-cells undergo profound hyperplasia during pregnancy to maintain maternal euglycemia. Failure to reprogram β-cells into a more replicative state has been found to underlie susceptibility to gestational diabetes mellitus (GDM). We recently identified a requirement for prolactin receptor (PRLR) signaling in the metabolic adaptations to pregnancy, where β-cell-specific PRLR knockout (βPRLRKO) mice exhibit a metabolic phenotype consistent with GDM. However, the underlying transcriptional program that is responsible for the PRLR-dependent metabolic adaptations during gestation remains incompletely understood...
May 1, 2019: Endocrinology
Teak-Jung Oh, Abhinav Adhikari, Trefa Mohamad, Aiysha Althobaiti, Judith Davie
TBX2 and TBX3 function as repressors and are frequently implicated in oncogenesis. We have shown that TBX2 represses p21, p14/19, and PTEN in rhabdomyosarcoma (RMS) and skeletal muscle but the function and regulation of TBX3 were unclear. We show that TBX3 directly represses TBX2 in RMS and skeletal muscle. TBX3 overexpression impairs cell growth and migration and we show that TBX3 is directly repressed by the polycomb repressive complex 2 (PRC2), which methylates histone H3 lysine 27 (H3K27me ). We found that TBX3 promotes differentiation only in the presence of early growth response factor 1 (EGR1), which is differentially expressed in RMS and is also a target of the PRC2 complex...
April 12, 2019: Oncogenesis
Krupa S Jani, Siddhant U Jain, Eva J Ge, Katharine L Diehl, Stefan M Lundgren, Manuel M Müller, Peter W Lewis, Tom W Muir
Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and trimethylation of lysine 27 on histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of developmentally important genes. Intriguingly, H3K27me3 is mutually exclusive with H3K36 trimethylation on the same histone tail. Disruptions in this cross-talk result in aberrant H3K27/H3K36 methylation patterns and altered transcriptional profiles that have been implicated in tumorigenesis and other disease states...
April 23, 2019: Proceedings of the National Academy of Sciences of the United States of America
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