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https://www.readbyqxmd.com/read/28097693/distinguishing-between-biochemical-and-cellular-function-are-there-peptide-signatures-for-cellular-function-of-proteins
#1
Shruti Jain, Kausik Bhattacharyya, Rachit Bakshi, Ankita Narang, Vani Brahmachari
The genome annotation and identification of gene function depends on conserved biochemical activity. However, in the cell, proteins with the same biochemical function can participate in different cellular pathways and cannot complement one another. Similarly, two proteins of very different biochemical functions are put in the same class of cellular function; for example, the classification of a gene as an oncogene or a tumour suppressor gene is not related to its biochemical function, but is related to its cellular function...
January 18, 2017: Proteins
https://www.readbyqxmd.com/read/28095419/prc2-represses-hormone-induced-somatic-embryogenesis-in-vegetative-tissue-of-arabidopsis-thaliana
#2
Iva Mozgová, Rafael Muñoz-Viana, Lars Hennig
Many plant cells can be reprogrammed into a pluripotent state that allows ectopic organ development. Inducing totipotent states to stimulate somatic embryo (SE) development is, however, challenging due to insufficient understanding of molecular barriers that prevent somatic cell dedifferentiation. Here we show that Polycomb repressive complex 2 (PRC2)-activity imposes a barrier to hormone-mediated transcriptional reprogramming towards somatic embryogenesis in vegetative tissue of Arabidopsis thaliana. We identify factors that enable SE development in PRC2-depleted shoot and root tissue and demonstrate that the establishment of embryogenic potential is marked by ectopic co-activation of crucial developmental regulators that specify shoot, root and embryo identity...
January 17, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28094282/evidence-of-neofunctionalization-after-the-duplication-of-the-highly-conserved-polycomb-group-gene-caf1-55-in-the-obscura-group-of-drosophila
#3
Juan M Calvo-Martín, Montserrat Papaceit, Carmen Segarra
Drosophila CAF1-55 protein is a subunit of the Polycomb repressive complex PRC2 and other protein complexes. It is a multifunctional and evolutionarily conserved protein that participates in nucleosome assembly and remodelling, as well as in the epigenetic regulation of a large set of target genes. Here, we describe and analyze the duplication of Caf1-55 in the obscura group of Drosophila. Paralogs exhibited a strong asymmetry in evolutionary rates, which suggests that they have evolved according to a neofunctionalization process...
January 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28092155/discovery-of-first-in-class-potent-and-orally-bioavailable-eed-inhibitor-with-robust-anti-cancer-efficacy
#4
Ying Huang, Jeff Zhang, Zhengtian Yu, Hailong Zhang, Youzhen Wang, Andreas Lingel, Wei Qi, X Justin Gu, Kehao Zhao, Michael David Shultz, Long Wang, Xingnian Fu, Yongfeng Sun, Qiong Zhang, Xiangqing Jiang, Jiang-Wei Zhang, Chunye Zhang, Ling Li, Jue Zeng, Lijian Feng, Chao Zhang, Yueqin Liu, Man Zhang, Lijun Zhang, Mengxi Zhao, Zhenting Gao, Xianghui Liu, Douglas Fang, Haibing Guo, Yuan Mi, Tobias Gabriel, Michael P Dillon, Peter Atadja, Counde Oyang
Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit Polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (Tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective and orally bioavailable EED inhibitor EED226 (compound 43)...
January 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28091603/repo-man-pp1-regulates-heterochromatin-formation-in-interphase
#5
Inês J de Castro, James Budzak, Maria L Di Giacinto, Lorena Ligammari, Ezgi Gokhan, Christos Spanos, Daniela Moralli, Christine Richardson, Jose I de Las Heras, Silvia Salatino, Eric C Schirmer, Katharine S Ullman, Wendy A Bickmore, Catherine Green, Juri Rappsilber, Sarah Lamble, Martin W Goldberg, Veronica Vinciotti, Paola Vagnarelli
Repo-Man is a protein phosphatase 1 (PP1) targeting subunit that regulates mitotic progression and chromatin remodelling. After mitosis, Repo-Man/PP1 remains associated with chromatin but its function in interphase is not known. Here we show that Repo-Man, via Nup153, is enriched on condensed chromatin at the nuclear periphery and at the edge of the nucleopore basket. Repo-Man/PP1 regulates the formation of heterochromatin, dephosphorylates H3S28 and it is necessary and sufficient for heterochromatin protein 1 binding and H3K27me3 recruitment...
January 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28087711/ctcf-mediated-topological-boundaries-during-development-foster-appropriate-gene-regulation
#6
Varun Narendra, Milica Bulajić, Job Dekker, Esteban O Mazzoni, Danny Reinberg
The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28087428/polycomb-complexes-prc1-and-their-function-in-hematopoiesis
#7
REVIEW
Miguel Vidal, Katharzina Starowicz
Hematopoiesis, the process by which blood cells are continuously produced, is one of the best studied differentiation pathways. Hematological diseases are associated to reiterated mutations in genes encoding important gene expression regulators, including chromatin regulators. Among them, the Polycomb group (PcG) of proteins is an essential system of gene silencing involved in the maintenance of cell identities during differentiation. PcG proteins assemble into two major types of Polycomb repressive complexes (PRC) endowed with distinct histone tail modifying activities...
January 10, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28079973/a-regulatory-bmi1-let-7i-erk3-pathway-controls-the-motility-of-head-and-neck-cancer-cells
#8
Lobna Elkhadragy, Minyi Chen, Kennon Miller, Muh-Hwa Yang, Weiwen Long
Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells...
November 9, 2016: Molecular Oncology
https://www.readbyqxmd.com/read/28079155/dietary-phytochemical-peitc-restricts-tumor-development-via-modulation-of-epigenetic-writers-and-erasers
#9
Jung Eun Park, Yang Sun, Sai Kiang Lim, James P Tam, Matthijs Dekker, Hong Chen, Siu Kwan Sze
Dietary intake of bioactive phytochemicals including the cruciferous vegetable derivative phenethyl isothiocyanate (PEITC) can reduce risk of human cancers, but possible epigenetic mechanisms of these effects are yet unknown. We therefore sought to identify the molecular basis of PEITC-mediated epigenetic tumor restriction. Colon cancer cells treated with low-dose PEITC for >1 month exhibited stable alterations in expression profile of epigenetic writers/erasers and chromatin-binding of histone deacetylases (HDACs) and Polycomb-group (PcG) proteins...
January 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28073915/ube2e1-ubch6-is-a-critical-in-vivo-e2-for-the-prc1-catalyzed-ubiquitination-of-h2a-at-k119
#10
Keith Wheaton, Feroz Sarkari, Beena Stanly Johns, Hossein Davarinejad, Olga Egorova, Lilia Kaustov, Brian Raught, Vivian Saridakis, Yi Sheng
UbE2E1/UbcH6 is an E2 ubiquitin conjugating enzyme that is regulated by USP7. We identified UbE2E1 as a novel component of Polycomb Repressive Complex 1 (PRC1), the E3 ligase complex responsible for histone H2A ubiquitination and gene silencing. We demonstrate that UbE2E1 is critical for the mono-ubiquitination of H2A at residue K119 (uH2AK119) through its association with the PRC1 complex. UbE2E1 interacts with PRC1 subunits including Ring1A and Ring1B. Overexpression of UbE2E1 results in increased levels of uH2AK119 whereas overexpression of catalytically inactive UbE2E1C131A or UbE2E1 knockdown results in decreased levels of uH2AK119...
January 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28072869/discovery-and-molecular-basis-of-a-diverse-set-of-polycomb-repressive-complex-2-inhibitors-recognition-by-eed
#11
Ling Li, Hailong Zhang, Man Zhang, Mengxi Zhao, Lijian Feng, Xiao Luo, Zhenting Gao, Ying Huang, Ophelia Ardayfio, Ji-Hu Zhang, Ying Lin, Hong Fan, Yuan Mi, Guobin Li, Lei Liu, Leying Feng, Fangjun Luo, Lin Teng, Wei Qi, Johannes Ottl, Andreas Lingel, Dirksen E Bussiere, Zhengtian Yu, Peter Atadja, Chris Lu, En Li, Justin Gu, Kehao Zhao
Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3), and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model...
2017: PloS One
https://www.readbyqxmd.com/read/28069891/governing-the-silencing-state-of-chromatin-the-roles-of-polycomb-repressive-complex-1-in-arabidopsis
#12
Xianli Yang, Aizi Tong, Bowen Yan, Xiaoxue Wang
Polycomb group proteins form multiple protein complexes such as polycomb repressive complex (PRC) 1 and PRC2, which repress the expression of thousands of genes. PRC1 and PRC2 are essential for normal development in Arabidopsis Recently, significant progress has been made in understanding the functions and regulatory mechanisms of PRC1. In this review, we focus on the discovery of the composition of PRC1, functions of its components, the recruitment of PRC1 to target genes, and the control of PRC1 function in Arabidopsis Perspectives on dissecting the roles of PRC1 in plant gene expression and development are also given...
January 9, 2017: Plant & Cell Physiology
https://www.readbyqxmd.com/read/28068325/trim28-interacts-with-ezh2-and-swi-snf-to-activate-genes-that-promote-mammosphere-formation
#13
J Li, Y Xi, W Li, R L McCarthy, S A Stratton, W Zou, W Li, S Y Dent, A K Jain, M C Barton
Histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) is generally associated with H3K27 methylation and gene silencing, as a member of the polycomb repressor 2 (PRC2) complex. Immunoprecipitation and mass spectrometry of the EZH2-protein interactome in estrogen receptor positive, breast cancer-derived MCF7 cells revealed EZH2 interactions with subunits of chromatin remodeler SWI/SNF complex and TRIM28, which formed a complex with EZH2 distinct from PRC2. Unexpectedly, transcriptome profiling showed that EZH2 primarily activates, rather than represses, transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28067271/praja1-e3-ubiquitin-ligase-promotes-skeletal-myogenesis-through-degradation-of-ezh2-upon-p38%C3%AE-activation
#14
Silvia Consalvi, Arianna Brancaccio, Alessandra Dall'Agnese, Pier Lorenzo Puri, Daniela Palacios
Polycomb proteins are critical chromatin modifiers that regulate stem cell differentiation via transcriptional repression. In skeletal muscle progenitors Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), contributes to maintain the chromatin of muscle genes in a repressive conformation, whereas its down-regulation allows the progression through the myogenic programme. Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28063196/asxl2-mutations-are-frequently-found-in-pediatric-aml-patients-with-t-8-21-runx1-runx1t1-and-associated-with-a-better-prognosis
#15
Genki Yamato, Norio Shiba, Kenichi Yoshida, Yuichi Shiraishi, Yusuke Hara, Kentaro Ohki, Jun Okubo, Haruna Okuno, Kenichi Chiba, Hiroko Tanaka, Akitoshi Kinoshita, Hiroshi Moritake, Nobutaka Kiyokawa, Daisuke Tomizawa, Myoung-Ja Park, Manabu Sotomatsu, Takashi Taga, Souichi Adachi, Akio Tawa, Keizo Horibe, Hirokazu Arakawa, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi
ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric AML patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0-17 years)...
January 7, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28052011/ezh2-inhibition-in-multiple-myeloma-downregulates-myeloma-associated-oncogenes-and-upregulates-micrornas-with-potential-tumor-suppressor-functions
#16
Mohammad Alzrigat, Alba Atienza Párraga, Prasoon Agarwal, Hadil Zureigat, Anders Österborg, Hareth Nahi, Anqi Ma, Jian Jin, Kenneth Nilsson, Fredrik Öberg, Antonia Kalushkova, Helena Jernberg-Wiklund
Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM...
December 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/28049731/essential-role-for-polycomb-group-protein-pcgf6-in-embryonic-stem-cell-maintenance-and-a-noncanonical-polycomb-repressive-complex-1-prc1-integrity
#17
Wukui Zhao, Huan Tong, Yikai Huang, Yun Yan, Huajian Teng, Yin Xia, Qing Jiang, Jinzhong Qin
The Polycomb group (PcG) proteins have an important role in controlling the expression of key genes implicated in embryonic development, differentiation and decision of cell fates. Emerging evidence suggests that Polycomb repressive complexes 1 (PRC1) is defined by the six Polycomb group RING finger protein (Pcgf) paralogs and Pcgf proteins can assemble into noncanonical PRC1 complexes. However, little is known about the precise mechanisms of differently composed noncanonical PRC1 in the maintenance of the pluripotent cell state...
January 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28049701/three-dimensional-genome-organization-and-function-in-drosophila
#18
Yuri B Schwartz, Giacomo Cavalli
Understanding how the metazoan genome is used during development and cell differentiation is one of the major challenges in the postgenomic era. Early studies in Drosophila suggested that three-dimensional (3D) chromosome organization plays important regulatory roles in this process and recent technological advances started to reveal connections at the molecular level. Here we will consider general features of the architectural organization of the Drosophila genome, providing historical perspective and insights from recent work...
January 2017: Genetics
https://www.readbyqxmd.com/read/28049658/stage-and-subunit-specific-functions-of-polycomb-repressive-complex-2-in-bladder-urothelial-formation-and-regeneration
#19
Chunming Guo, Zarine R Balsara, Warren G Hill, Xue Li
Urothelium is the protective lining of the urinary tract. The mechanisms underlying urothelial formation and maintenance are largely unknown. Here, we report the stage-specific roles of PRC2 epigenetic regulators in embryonic and adult urothelial progenitors. Without Eed, the obligatory subunit of PRC2, embryonic urothelial progenitors demonstrate reduced proliferation with concomitant dysregulation of genes including Cdkn2a(p16), Cdkn2b(p15) and Shh. These mutants display premature differentiation of Keratin 5-positive (Krt5(+)) basal cells and ectopic expression of squamous-like differentiation markers...
January 3, 2017: Development
https://www.readbyqxmd.com/read/28044469/epigenetic-silencing-and-activation-of-transcription-influence-on-the-radiation-sensitivity-of-glioma-cell-lines
#20
A Sak, D Kübler, K Bannik, M Groneberg, S Strunz, R Kriehuber, M Stuschke
PURPOSE: To uncover the role of EZH2 and its opponent ASHL2, a polycomb and trithorax group protein, respectively on the radioresponsiveness of glioma cell lines. MATERIAL AND METHODS: Expression of EZH2 and ASHL2 was inhibited by siRNA in glioma cell lines. The effect on histone methylation, gene expression, DNA damage repair signaling, cell cycle checkpoints, apoptosis and tumor control were evaluated. RESULTS: Inhibition of EZH2 (EZH2i) led to a transcriptional dysregulation with upregulation of 544 and downregulation of 445 genes...
January 3, 2017: International Journal of Radiation Biology
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