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M Wassef, R Margueron
Genome sequencing of large cohorts of tumors has revealed that mutations in genes encoding chromatin regulators are frequent in cancer. However, the precise contribution of these mutations to tumor development often remains elusive. Here, we review the current knowledge concerning alterations of the Polycomb machinery in cancer, with a particular focus on the Polycomb Repressive Complex 2 (PRC2), a key chromatin modifier involved in the maintenance of transcriptional silencing. A broad variety of alterations can impair PRC2 activity yet, overall, only one type of alteration is found in a given class of tumor...
October 11, 2016: Journal of Molecular Biology
Rishi G Vaswani, Victor S Gehling, Les A Dakin, Andrew Cook, Christopher G Nasveschuk, Martin Duplessis, Priyadarshini Iyer, Srividya Balasubramanian, Feng Zhao, Andrew C Good, Robert Campbell, Christina Lee, Nico Cantone, Richard T Cummings, Emmanuel Normant, Steven F Bellon, Brian K Albrecht, Jean-Christophe P Harmange, Patrick Trojer, James E Audia, Ying Zhang, Neil Justin, Shuyang Chen, Jon Wilson, Steve Gamblin
Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0...
October 14, 2016: Journal of Medicinal Chemistry
Simon Hauri, Federico Comoglio, Makiko Seimiya, Moritz Gerstung, Timo Glatter, Klaus Hansen, Ruedi Aebersold, Renato Paro, Matthias Gstaiger, Christian Beisel
Polycomb group (PcG) proteins are major determinants of gene silencing and epigenetic memory in higher eukaryotes. Here, we systematically mapped the human PcG complexome using a robust affinity purification mass spectrometry approach. Our high-density protein interaction network uncovered a diverse range of PcG complexes. Moreover, our analysis identified PcG interactors linking them to the PcG system, thus providing insight into the molecular function of PcG complexes and mechanisms of recruitment to target genes...
October 4, 2016: Cell Reports
Nathan R Rose, Hamish W King, Neil P Blackledge, Nadezda A Fursova, Katherine Ji Ember, Roman Fischer, Benedikt M Kessler, Robert J Klose
Polycomb group (PcG) proteins function as chromatin-based transcriptional repressors that are essential for normal gene regulation during development. However, how these systems function to achieve transcriptional regulation remains very poorly understood. Here, we discover that the histone H2AK119 E3 ubiquitin ligase activity of Polycomb repressive complex 1 (PRC1) is defined by the composition of its catalytic subunits and is highly regulated by RYBP/YAF2-dependent stimulation. In mouse embryonic stem cells, RYBP plays a central role in shaping H2AK119 mono-ubiquitylation at PcG targets and underpins an activity-based communication between PRC1 and Polycomb repressive complex 2 (PRC2) which is required for normal histone H3 lysine 27 trimethylation (H3K27me3)...
October 5, 2016: ELife
Omer Durak, Fan Gao, Yea Jin Kaeser-Woo, Richard Rueda, Anthony J Martorell, Alexi Nott, Carol Y Liu, L Ashley Watson, Li-Huei Tsai
De novo mutations in CHD8 are strongly associated with autism spectrum disorder, but the basic biology of CHD8 remains poorly understood. Here we report that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice. Transcriptome analysis revealed that while Chd8 stimulates the transcription of cell cycle genes, it also precludes the induction of neural-specific genes by regulating the expression of PRC2 complex components...
October 3, 2016: Nature Neuroscience
Claire Barnes, Aditi Kanhere
Recent advances in next-generation sequencing have revealed that majority of the human genome is transcribed into long and short RNA (ncRNA) transcripts. Many ncRNAs function by interacting with proteins and forming regulatory complexes. RNA-protein interactions are vital in controlling core cellular processes like transcription and translation. Therefore identifying proteins that interact with ncRNAs is central to deciphering ncRNA functions. Here we describe an RNA-protein pull-down assay, which enables the identification of proteins that interact with an RNA under study...
2016: Methods in Molecular Biology
Na Keum Lee, Jung Hwa Lee, Won Kyu Kim, Seongju Yun, Young Hoon Youn, Chan Hyuk Park, Yun Young Choi, Hogeun Kim, Sang Kil Lee
HOTAIR, a long non-coding RNA (lncRNA), plays a crucial role in tumor initiation and metastasis by interacting with the PRC2 complex and the modulation of its target genes. The role of HOTAIR in gastrointestinal stromal tumors (GISTs) is remains unclear. Herein we investigate the mechanism of HOTAIR in the genesis and promotion of GISTs. The expression of HOTAIR was found to be higher in surgically resected high-risk GISTs than that in low- and intermediate-risk GISTs. Using GIST-T1 and GIST882 cells, we demonstrated that HOTAIR repressed apoptosis, was associated with cell cycle progression, and controlled the invasion and migration of GIST cells...
September 21, 2016: Oncotarget
Itys Comet, Eva M Riising, Benjamin Leblanc, Kristian Helin
Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb repressive complex 2 (PRC2), has attracted broad research attention in the past few years because of its involvement in the development and maintenance of many types of cancer and the use of specific EZH2 inhibitors in clinical trials. Several observations show that PRC2 can have both oncogenic and tumour-suppressive functions. We propose that these apparently opposing roles of PRC2 in cancer are a consequence of the molecular function of the complex in maintaining, rather than specifying, the transcriptional repression state of its several thousand target genes...
September 23, 2016: Nature Reviews. Cancer
Ming Sun, Fengqi Nie, Yunfei Wang, Zhihong Zhang, Jiakai Hou, Dandan He, Min Xie, Wei De, Zhaoxia Wang, Jun Wang
Long noncoding RNAs (lncRNA) have been implicated in human cancer but their mechanisms of action are mainly undocumented. In this study, we investigated lncRNA alterations that contribute to gastric cancer (GC) through an analysis of TCGA RNA sequencing data and other publicly available microarray data. Here we report the GC-associated lncRNA HOXA11-AS as a key regulator of GC development and progression. Patients with high HOXA11-AS expression had a shorter survival and poorer prognosis. In vitro and in vivo assays of HOXA11-AS alterations revealed a complex integrated phenotype affecting cell growth, migration, invasion and apoptosis...
September 20, 2016: Cancer Research
Miguel de Lucas, Li Pu, Gina Marie Turco, Allie Gaudinier, Ana Karina Marao, Hirofumi Harashima, Dahae Kim, Mily Ron, Keiko Sugimoto, Francois M Roudier, Siobhan M Brady
Spatiotemporal regulation of transcription is fine-tuned at multiple levels, including chromatin compaction. Polycomb Repressive Complex 2 (PRC2) catalyzes the trimethylation of Histone 3 at lysine 27 (H3K27me3), which is the hallmark of a repressive chromatin state. Multiple PRC2 complexes have been reported in Arabidopsis thaliana to control the expression of genes involved in developmental transitions and maintenance of organ identity. Here, we show that PRC2 member genes display complex spatiotemporal gene expression patterns and function in root meristem and vascular cell proliferation and specification...
September 20, 2016: Plant Cell
Masamitsu N Asaka, Atsushi Kawaguchi, Yuri Sakai, Kotaro Mori, Kyosuke Nagata
The organization of nuclear domains is crucial for biological events including virus infection. Newly synthesized influenza viral genome forms viral ribonucleoprotein (vRNP) complexes and is exported from the nucleus to the cytoplasm through a CRM1-dependent pathway mediated by viral proteins M1 and NS2. However, the spatio-temporal regulation of the progeny vRNP in the nucleus is still unclear. Here we found that polycomb repressive complex 2 (PRC2), which contains a methyltransferase subunit EZH2 and catalyzes histone H3K27me3 for the formation of facultative heterochromatin, is a positive factor for the virus production...
2016: Scientific Reports
Vincent Loubiere, Anna Delest, Aubin Thomas, Boyan Bonev, Bernd Schuettengruber, Satish Sati, Anne-Marie Martinez, Giacomo Cavalli
Polycomb group proteins form two main complexes, PRC2 and PRC1, which generally coregulate their target genes. Here we show that PRC1 components act as neoplastic tumor suppressors independently of PRC2 function. By mapping the distribution of PRC1 components and trimethylation of histone H3 at Lys27 (H3K27me3) across the genome, we identify a large set of genes that acquire PRC1 in the absence of H3K27me3 in Drosophila larval tissues. These genes massively outnumber canonical targets and are mainly involved in the regulation of cell proliferation, signaling and polarity...
September 19, 2016: Nature Genetics
Kai-Oliver Henrich, Sebastian Bender, Maral Saadati, Daniel Dreidax, Moritz Gartlgruber, Chunxuan Shao, Carl Herrmann, Manuel Wiesenfarth, Martha Parzonka, Lea Wehrmann, Matthias Fischer, David J Duffy, Emma Bell, Alica Torkov, Peter Schmezer, Christoph Plass, Thomas Höfer, Axel Benner, Stefan M Pfister, Frank Westermann
The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor- and cell line-derived global histone modification analyses and epigenetic drug treatment in vitro We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN Transcriptome integration and histone modification-based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk-associated transcriptional deregulation...
September 15, 2016: Cancer Research
Giorgio Oliviero, Gerard L Brien, Ariane Watson, Gundula Streubel, Emilia Jerman, Darrell Andrews, Benjamin Doyle, Nayla Munawar, Kieran Wynne, John Crean, Adrian P Bracken, Gerard Cagney
Polycomb proteins assemble to form complexes with important roles in epigenetic regulation. The Polycomb Repressive Complex 2 (PRC2) modulates the di- and tri-methylation of lysine 27 on histone H3, each of which are associated with gene repression. Although three subunits, EZH1/2, SUZ12 and EED, form the catalytic core of PRC2, a wider group of proteins associate with low stoichiometry. This raises the question of whether dynamic variation of the PRC2 interactome results in alternative forms of the complex during differentiation...
September 15, 2016: Molecular & Cellular Proteomics: MCP
Huafeng Xie, Cong Peng, Jialiang Huang, Bin E Li, Woojin Kim, Elenoe C Smith, Yuko Fujiwara, Jun Qi, Giulia Cheloni, Partha P Das, Minh Nguyen, Shaoguang Li, James E Bradner, Stuart H Orkin
Tyrosine kinase inhibitors (TKIs) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia initiating cells (LICs) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs, required for colony formation, and survival and cell cycle progression of CML cell lines. A critical role for Ezh2 is supported by genetic studies in a mouse CML model...
September 14, 2016: Cancer Discovery
Danfeng Sun, Yanwei Lin, Jie Hong, Haoyan Chen, Nisha Nagarsheth, Dongjun Peng, Shuang Wei, Emina Huang, Jingyuan Fang, Ilona Kryczek, Weiping Zou
Th22 cells traffic to and retain in the colon cancer microenvironment, and target core stem cell genes and promote colon cancer stemness via STAT3 and H3K79me2 signaling pathway and contribute to colon carcinogenesis. However, whether Th22 cells affect colon cancer cell proliferation and apoptosis remains unknown. We studied the interaction between Th22 cells and colon cancer cells in the colon cancer microenvironment. Colon cancer proliferation was examined by flow cytometry analysis and H(3) thymidine incorporation...
August 2016: Oncoimmunology
Zhihua Wang, Xiao-Jing Zhang, Yan-Xiao Ji, Peng Zhang, Ke-Qiong Deng, Jun Gong, Shuxun Ren, Xinghua Wang, Iris Chen, He Wang, Chen Gao, Tomohiro Yokota, Yen Sin Ang, Shen Li, Ashley Cass, Thomas M Vondriska, Guangping Li, Arjun Deb, Deepak Srivastava, Huang-Tian Yang, Xinshu Xiao, Hongliang Li, Yibin Wang
Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy...
October 2016: Nature Medicine
Ji Sook Kim, Ji Hyung Chae, Yong-Pil Cheon, Chul Geun Kim
Maintaining stemness and permitting differentiation mediated by combinations of transcription factors (TFs) are key aspects of mammalian spermatogenesis. It has been established that yin yang 1 (YY1), a target factor of mammalian polycomb repressive complex 2 (PRC2) and a regulator of stemness, is involved in the stable maintenance of prophase stage spermatocytes. Recently, we have demonstrated that the TF CP2c partners with YY1 in some cells to antagonistically regulate the other protein's function. To date, the functional roles of YY1 and CP2c in spermatogonial stem cells and their derived germ cells remain unclear...
September 6, 2016: Acta Histochemica
Zsolt Toth, Bernadett Papp, Kevin Brulois, Youn Jung Choi, Shou-Jiang Gao, Jae U Jung
One of the hallmarks of the latent phase of Kaposi's sarcoma-associated herpesvirus (KSHV) infection is the global repression of lytic viral gene expression. Following de novo KSHV infection, the establishment of latency involves the chromatinization of the incoming viral genomes and recruitment of the host Polycomb repressive complexes (PRC1 and PRC2) to the promoters of lytic genes, which is accompanied by the inhibition of lytic genes. However, the mechanism of how PRCs are recruited to the KSHV episome is still unknown...
September 2016: PLoS Pathogens
Stefanie Seelk, Irene Adrian-Kalchhauser, Balázs Hargitai, Martina Hajduskova, Silvia Gutnik, Baris Tursun, Rafal Ciosk
Cell-fate reprograming is at the heart of development, yet very little is known about the molecular mechanisms promoting or inhibiting reprograming in intact organisms. In the C. elegans germline, reprograming germ cells into somatic cells requires chromatin perturbation. Here, we describe that such reprograming is facilitated by GLP-1/Notch signaling pathway. This is surprising, since this pathway is best known for maintaining undifferentiated germline stem cells/progenitors. Through a combination of genetics, tissue-specific transcriptome analysis, and functional studies of candidate genes, we uncovered a possible explanation for this unexpected role of GLP-1/Notch...
September 7, 2016: ELife
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