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polycomb repressor complex

Vivian Y Poon, Minxia Gu, Fang Ji, Antonius M VanDongen, Marc Fivaz
BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNAs that are emerging as important post-transcriptional regulators of neuronal and synaptic development. The precise impact of miRNAs on presynaptic function and neurotransmission remains, however, poorly understood. RESULTS: Here, we identify miR-27b-an abundant neuronal miRNA implicated in neurological disorders-as a global regulator of the presynaptic transcriptome. miR-27b influences the expression of three quarters of genes associated with presynaptic function in cortical neurons...
October 4, 2016: BMC Genomics
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
Stéphanie Käser-Pébernard, Catherine Pfefferli, Caroline Aschinger, Chantal Wicky
BACKGROUND: The nucleosome remodeling and deacetylase complex promotes cell fate decisions throughout embryonic development. Its core enzymatic subunit, the SNF2-like ATPase and Helicase Mi2, is well conserved throughout the eukaryotic kingdom and can be found in multiple and highly homologous copies in all vertebrates and some invertebrates. However, the reasons for such duplications and their implications for embryonic development are unknown. RESULTS: Here we studied the two C...
2016: Epigenetics & Chromatin
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
Tatyana G Kahn, Eshagh Dorafshan, Dorothea Schultheis, Aman Zare, Per Stenberg, Ingolf Reim, Vincenzo Pirrotta, Yuri B Schwartz
Polycomb Group (PcG) proteins are epigenetic repressors essential for control of development and cell differentiation. They form multiple complexes of which PRC1 and PRC2 are evolutionary conserved and obligatory for repression. The targeting of PRC1 and PRC2 is poorly understood and was proposed to be hierarchical and involve tri-methylation of histone H3 (H3K27me3) and/or monoubiquitylation of histone H2A (H2AK118ub). Here, we present a strict test of this hypothesis using the Drosophila model. We discover that neither H3K27me3 nor H2AK118ub is required for targeting PRC complexes to Polycomb Response Elements (PREs)...
August 23, 2016: Nucleic Acids Research
Julia I Qüesta, Jie Song, Nuno Geraldo, Hailong An, Caroline Dean
The determinants that specify the genomic targets of Polycomb silencing complexes are still unclear. Polycomb silencing of Arabidopsis FLOWERING LOCUS C (FLC) accelerates flowering and involves a cold-dependent epigenetic switch. Here we identify a single point mutation at an intragenic nucleation site within FLC that prevents this epigenetic switch from taking place. The mutation blocks nucleation of plant homeodomain-Polycomb repressive complex 2 (PHD-PRC2) and indicates a role for the transcriptional repressor VAL1 in the silencing mechanism...
July 29, 2016: Science
Jin Young Lee, Kyung-Rok Yu, Hyung-Sik Kim, Insung Kang, Jae-Jun Kim, Byung-Chul Lee, Soon Won Choi, Ji-Hee Shin, Yoojin Seo, Kyung-Sun Kang
For the application of mesenchymal stem cells (MSCs) as clinical therapeutics, the regulation of cellular aging is important to protect hMSCs from an age-associated decline in their function. In this study, we evaluated the effects of hypoxia on cellular senescence and the immunomodulatory abilities of hUCB-MSCs. Hypoxic-cultured hUCB-MSCs showed enhanced proliferation and had increased immunosuppressive effects on mitogen-induced mononuclear cell proliferation. We found that BMI1, a member of the polycomb repressive complex protein group, showed increased expression in hypoxic-cultured hUCB-MSCs, and the further knock-down of BMI1 in hypoxic cells induced decreased proliferative and immunomodulatory abilities in hUCB-MSCs, along with COX-2/PGE2 down-regulation...
August 2016: Aging
C Battistelli, C Cicchini, L Santangelo, A Tramontano, L Grassi, F J Gonzalez, V de Nonno, G Grassi, L Amicone, M Tripodi
The transcription factor Snail is a master regulator of cellular identity and epithelial-to-mesenchymal transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail-specific binding sites is unclear. Here we report that the long non-coding RNA (lncRNA) HOTAIR (for HOX Transcript Antisense Intergenic RNA) mediates a physical interaction between Snail and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2 and the main writer of chromatin-repressive marks...
July 25, 2016: Oncogene
Vladimir A Botchkarev, Andrei N Mardaryev
The Polycomb group proteins are transcriptional repressors that are critically important in the control of stem cell activity and maintenance of the identity of differentiated cells. Polycomb proteins interact with each other to form chromatin-associated repressive complexes (Polycomb repressive complexes 1 and 2) leading to chromatin compaction and gene silencing. However, the roles of the distinct components of the Polycomb repressive complex 2 in the control of skin development and keratinocyte differentiation remain obscure...
August 2016: Journal of Investigative Dermatology
Pan Yu, Yawen Guo, Maimaiti Yusufu, Zeming Liu, Shan Wang, Xingjie Yin, Gongling Peng, Longqiang Wang, Xiangwang Zhao, Hui Guo, Tao Huang, Chunping Liu
EZH2, the catalytic subunit of polycomb repressor complex 2, has oncogenic properties, whereas RASSF2A, a Ras association domain family protein, has a tumor suppressor role in many types of human cancer. However, the interrelationship between these two genes remains unclear. Here, we showed that the downregulation of EZH2 reduces CpG island methylation of the RASSF2A promoter, thereby leading to increased RASSF2A expression. Our findings also showed that knockdown of EZH2 increased RASSF2A expression in the human breast cancer cell line MCF-7 in cooperation with DNMT1...
October 2016: Cell Biology International
Stefan Nagel, Claudia Pommerenke, Corinna Meyer, Maren Kaufmann, Hans G Drexler, Roderick A F MacLeod
Recently, we identified deregulated expression of the B-cell specific transcription factor MEF2C in T-cell acute lymphoid leukemia (T-ALL). Here, we performed sequence analysis of a regulatory upstream section of MEF2C in T-ALL cell lines which, however, proved devoid of mutations. Unexpectedly, we found strong conservation between the regulatory upstream region of MEF2C (located at chromosomal band 5q14) and an intergenic stretch at 7q11 located between STAG3L4 and AUTS2, covering nearly 20 kb. While the non-coding gene STAG3L4 was inconspicuously expressed, AUTS2 was aberrantly upregulated in 6% of T-ALL patients (public dataset GSE42038) and in 3/24 T-ALL cell lines, two of which represented very immature differentiation stages...
June 13, 2016: Oncotarget
Gaetano Gargiulo, Elisabetta Citterio, Michela Serresi
The Polycomb transcriptional repressors regulate normal tissue homeostasis and their function is often hijacked during oncogenesis. We recently uncovered the Polycomb repressive complex-2 (PRC2) genes Ezh2 and Eed as oncogenotype-dependent cancer genes. Notably, within the same oncogenotype, PRC2 dosage modulates lung tumor homeostasis and critically impacts non-tumor tissue function.
May 2016: Molecular & Cellular Oncology
Zahid Nawaz, Vikas Patil, Anjali Arora, Alangar S Hegde, Arimappamagan Arivazhagan, Vani Santosh, Kumaravel Somasundaram
Glioblastomas (GBM) are the most malignant form of astrocytomas which are difficult to treat and portend a grave clinical course and poor prognosis. In this study, we identified Chromobox homolog 7 (Cbx7), a member of Polycomb Repressive Complex 1 (PRC1), as a downregulated gene in GBM owing to its promoter hypermethylation. Bisulphite sequencing and methylation inhibitor treatment established the hypermethylation of Cbx7 in GBM. Exogenous overexpression of Cbx7 induced cell death, inhibited cell proliferation, colony formation and migration/invasion of the glioma cells...
2016: Scientific Reports
Zhongfei Li, Bin Li, Jian Liu, Zhihao Guo, Yuhao Liu, Yan Li, Wen-Hui Shen, Ying Huang, Hai Huang, Yijing Zhang, Aiwu Dong
Polycomb group proteins are important repressors of numerous genes in higher eukaryotes. However, the mechanism by which Polycomb group proteins are recruited to specific genes is poorly understood. In Arabidopsis, LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), also known as TERMINAL FLOWER 2, was originally proposed as a subunit of polycomb repressive complex 1 (PRC1) that could bind the tri-methylated lysine 27 of histone H3 (H3K27me3) established by the PRC2. In this work, we show that LHP1 mainly functions with PRC2 to establish H3K27me3, but not with PRC1 to catalyze monoubiquitination at lysine 119 of histone H2A...
June 7, 2016: Journal of Integrative Plant Biology
Vivien Schäfer, Jana Ernst, Jenny Rinke, Nils Winkelmann, James F Beck, Andreas Hochhaus, Bernd Gruhn, Thomas Ernst
PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. The polycomb repressive complex 2 (PRC2) has been identified as one of the most frequently mutated epigenetic protein complexes in hematologic cancers. PRC2 acts as an epigenetic repressor through histone H3 lysine 27 trimethylation (H3K27me3), catalyzed by the histone methyltransferase enhancer of zeste homolog 2 protein (EZH2). METHODS: To study the prevalence and clinical impact of PRC2 aberrations in an unselected childhood ALL cohort (n = 152), we performed PRC2 mutational screenings by Sanger sequencing and promoter methylation analyses by quantitative pyrosequencing for the three PRC2 core component genes EZH2, suppressor of zeste 12 (SUZ12), and embryonic ectoderm development (EED)...
July 2016: Journal of Cancer Research and Clinical Oncology
Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-Gibbon, Pao-Yang Chen, Michael Thompson, Heather Christofk, David B Agus, Daniel Ruderman, Parag Mallick, Matteo Pellegrini
BACKGROUND: The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in drug resistance is less well understood. To investigate mechanisms of drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by drug dose escalation. METHODS: Dose escalation of the alkylating agent mafosfamide was used to create a series of increasingly drug-resistant mouse Burkitt's lymphoma cell lines...
2016: Genome Medicine
M Wiese, F Schill, D Sturm, S Pfister, E Hulleman, S A Johnsen, C M Kramm
BACKGROUND: Glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) belong to the most aggressive cancers in children with poor prognosis and limited therapeutic options. Therapeutic targeting of epigenetic proteins may offer new treatment options. Preclinical studies identified Enhancer of Zeste Homolog 2 (EZH2) within polycomb repressor complex 2 (PRC2) as a potential epigenetic anti-tumor target in adult GBM cells but similar inhibition studies in pediatric GBM/DIPG were still missing...
April 2016: Klinische Pädiatrie
Xiao-Qing Li, Wei-Peng He, Wen-Hui Hou, Jie-Wei Chen, Rong-Rong Fan, Lin-Jing Yuan, Gui-Ping Yang, Mu-Yan Cai, Li Chen, Jie Li, Shan-Yang He, Dan Xie, Guo-Fen Yang, Ze-Shan You
It has been reported that RNF2, a core member of the polycomb repressor complex 1 (PRC1) complex, is frequently overexpressed in several types of human cancers. However, abnormalities in RNF2 in ovarian carcinoma and its potential clinical/prognostic significance have not been elucidated. In this study, immunohistochemistry and fluorescence in situ hybridization were employed to examine the protein expression and amplification status of RNF2 in 30 normal ovaries, 30 ovarian cystadenomas, 40 borderline ovarian tumors and 170 ovarian carcinomas...
April 25, 2016: Oncotarget
Thaleia Papadopoulou, Aysegül Kaymak, Sergi Sayols, Holger Richly
Mediator is considered an enhancer of RNA-Polymerase II dependent transcription but its function and regulation in pluripotent mouse embryonic stem cells (mESCs) remains unresolved. One means of controlling the function of Mediator is provided by the binding of the Cdk8 module (Med12, Cdk8, Ccnc and Med13) to the core Mediator. Here we report that Med12 operates together with PRC1 to silence key developmental genes in pluripotency. At the molecular level, while PRC1 represses genes it is also required to assemble ncRNA containing Med12-Mediator complexes...
June 2, 2016: Cell Cycle
Ernest Palomer, Javier Carretero, Stefano Benvegnù, Carlos G Dotti, Mauricio G Martin
It has been recently described that in embryonic stem cells, the expression of some important developmentally regulated genes is repressed, but poised for fast activation under the appropriate stimuli. In this work we show that Bdnf promoters are repressed by Polycomb Complex 2 in mature hippocampal neurons, and basal expression is guaranteed by the coexistence with activating histone marks. Neuronal stimulation triggered by N-methyl-D-aspartate application induces the transcription of these promoters by H3K27Me3 demethylation and H3K27Me3 phosphorylation at Serine 28 leading to displacement of EZH2, the catalytic subunit of Polycomb Repressor Complex 2...
2016: Nature Communications
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