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https://www.readbyqxmd.com/read/29352142/fbxl10-contributes-to-the-development-of-diffuse-large-b-cell-lymphoma-by-epigenetically-enhancing-erk1-2-signaling-pathway
#1
Xiujuan Zhao, Xing Wang, Qian Li, Wanbiao Chen, Na Zhang, Yu Kong, Junqiang Lv, Lei Cao, Dan Lin, Xi Wang, Guogang Xu, Xudong Wu
Epigenetic modifiers have emerged as critical factors governing the biology of different cancers. Herein we show that FBXL10 (also called KDM2B or JHDM1B), an important member of Polycomb repressive complexes, is overexpressed in human diffuse large B-cell lymphoma (DLBCL) tissues and the derived cell lines. Knocking down FBXL10 by specific short hairpin RNAs in DLBCL cells inhibits cell proliferation and induces apoptosis in vitro. Moreover, FBXL10 depletion in DLBCL cells abrogates tumor growth in mouse xenograft models...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29351847/phosphorylation-of-ezh2-by-ampk-suppresses-prc2-methyltransferase-activity-and-oncogenic-function
#2
Lixin Wan, Kexin Xu, Yongkun Wei, Jinfang Zhang, Tao Han, Christopher Fry, Zhao Zhang, Yao Vickie Wang, Liyu Huang, Min Yuan, Weiya Xia, Wei-Chao Chang, Wen-Chien Huang, Chien-Liang Liu, Yuan-Ching Chang, Jinsong Liu, Yun Wu, Victor X Jin, Xiangpeng Dai, Jianfeng Guo, Jia Liu, Shulong Jiang, Jin Li, John M Asara, Myles Brown, Mien-Chie Hung, Wenyi Wei
Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts...
January 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29348366/structures-of-human-prc2-with-its-cofactors-aebp2-and-jarid2
#3
Vignesh Kasinath, Marco Faini, Simon Poepsel, Dvir Reif, Xinyu Ashlee Feng, Goran Stjepanovic, Ruedi Aebersold, Eva Nogales
Transcriptionally repressive histone H3K27 methylation by PRC2 (Polycomb repressive complex 2) is essential for cellular differentiation and development. Here we report cryo-EM structures of human PRC2 in two distinct, active states, while in complex with its cofactors JARID2 and AEBP2. Both cofactors mimic the binding of histone H3 tails. JARID2, methylated by PRC2, mimics a methylated H3 tail to stimulate PRC2 activity, while AEBP2 interacts with the RBAP48 subunit mimicking an unmodified H3 tail. SUZ12 interacts with all other subunits within the assembly and thus contributes to the stability of the complex...
January 18, 2018: Science
https://www.readbyqxmd.com/read/29345617/loss-of-functional-bap1-augments-sensitivity-to-trail-in-cancer-cells
#4
Krishna Kalyan Kolluri, Constantine Alifrangis, Neelam Kumar, Yuki Ishii, Stacey Price, Magali Michaut, Steven Williams, Syd Barthorpe, Howard Lightfoot, Sara Busacca, Annabel Sharkey, Zhenqiang Yuan, Elizabeth K Sage, Sabarinath Vallath, John Le Quesne, David A Tice, Doraid Alrifai, Sylvia von Karstedt, Antonella Montinaro, Naomi Guppy, David A Waller, Apostolos Nakas, Robert Good, Alan Holmes, Henning Walczak, Dean A Fennel, Mathew Garnett, Francesco Iorio, Lodewyk Wessels, Ultan McDermott, Samuel M Janes
Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants...
January 18, 2018: ELife
https://www.readbyqxmd.com/read/29342143/regulation-of-embryonic-haematopoietic-multipotency-by-ezh1
#5
Linda T Vo, Melissa A Kinney, Xin Liu, Yuannyu Zhang, Jessica Barragan, Patricia M Sousa, Deepak K Jha, Areum Han, Marcella Cesana, Zhen Shao, Trista E North, Stuart H Orkin, Sergei Doulatov, Jian Xu, George Q Daley
All haematopoietic cell lineages that circulate in the blood of adult mammals derive from multipotent haematopoietic stem cells (HSCs). By contrast, in the blood of mammalian embryos, lineage-restricted progenitors arise first, independently of HSCs, which only emerge later in gestation. As best defined in the mouse, 'primitive' progenitors first appear in the yolk sac at 7.5 days post-coitum. Subsequently, erythroid-myeloid progenitors that express fetal haemoglobin, as well as fetal lymphoid progenitors, develop in the yolk sac and the embryo proper, but these cells lack HSC potential...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29339543/genes-predisposed-to-dna-hypermethylation-during-acquired-resistance-to-chemotherapy-are-identified-in-ovarian-tumors-by-bivalent-chromatin-domains-at-initial-diagnosis
#6
Edward Curry, Constanze Zeller, Nahal Masrour, Darren Patten, John Gallon, Charlotte S Wilhelm-Benartzi, Sadaf Ghaem-Maghami, David D L Bowtell, Robert Brown
Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells aberrantly poised genes may facilitate changes in transcriptional states after exposure to anti-cancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3 and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue...
January 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29339137/oxygen-induced-alterations-in-the-expression-of-chromatin-modifying-enzymes-and-the-transcriptional-regulation-of-imprinted-genes
#7
William M Skiles, Avery Kester, Jane H Pryor, Mark E Westhusin, Michael C Golding, Charles R Long
Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a...
January 12, 2018: Gene Expression Patterns: GEP
https://www.readbyqxmd.com/read/29339121/hsf1-in-association-with-morc2-downregulates-argbp2-via-the-prc2-family-in-gastric-cancer-cells
#8
Yuxin Tong, Yan Li, Hui Gu, Chunyu Wang, Funan Liu, Yangguang Shao, Feng Li
Arg Kinase-binding protein 2 (ArgBP2) is considered to be a scaffold protein that coordinates multiple signaling pathways converging on cell adhesion and actin cytoskeletal organization. It also plays an important role in blocking cancer metastasis as a potential tumor suppressor. However, its regulation mechanisms in tumor migration, especially in gastric cancer, are not fully understood. Here, we identified an ArgBP2 enhancer and showed that heat shock factor 1 (HSF1) directly interacted with microrchidia CW-type zinc finger 2 (MORC2) and bound to the enhancer of ArgBP2...
January 12, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29337181/a-non-canonical-bcor-prc1-1-complex-represses-differentiation-programs-in-human-escs
#9
Zheng Wang, Micah D Gearhart, Yu-Wei Lee, Ishan Kumar, Bulat Ramazanov, Yan Zhang, Charles Hernandez, Alice Y Lu, Nils Neuenkirchen, Jingjing Deng, Jiaqi Jin, Yuval Kluger, Thomas A Neubert, Vivian J Bardwell, Natalia B Ivanova
Polycomb group proteins regulate self-renewal and differentiation in many stem cell systems. When assembled into two canonical complexes, PRC1 and PRC2, they sequentially deposit H3K27me3 and H2AK119ub histone marks and establish repressive chromatin, referred to as Polycomb domains. Non-canonical PRC1 complexes retain RING1/RNF2 E3-ubiquitin ligases but have unique sets of accessory subunits. How these non-canonical complexes recognize and regulate their gene targets remains poorly understood. Here, we show that the BCL6 co-repressor (BCOR), a member of the PRC1...
January 8, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29337063/bmi1-activates-wnt-signaling-in-colon-cancer-by-negatively-regulating-the-wnt-antagonist-idax
#10
Feiyue Yu, Chuanyi Zhou, Hui Zeng, Yabing Liu, Shangfu Li
Aberrant activation of Wnt signaling plays a critical role in the development of colon cancer. BMI, a component of the polycomb repressive complex (PRC1), is upregulated in various types of cancer and contributes to epigenetic silencing of tumor suppressors. In this study, we showed that BMI1 is upregulated in colon cancer tissues and cell lines. Overexpression of BMI1 in primary epithelial colon cells promotes cellular growth and activates WNT pathway, while BMI1 silencing in colon cancer cells represses these effects...
January 11, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29335012/the-polycomb-group-protein-ezh2-induces-epithelial-mesenchymal-transition-and-pluripotent-phenotype-of-gastric-cancer-cells-by-binding-to-pten-promoter
#11
Lu Gan, Midie Xu, Ruixi Hua, Cong Tan, Jieyun Zhang, Yiwei Gong, Zhenhua Wu, Weiwei Weng, Weiqi Sheng, Weijian Guo
BACKGROUND: The influences of oncogenic Ezh2 on the progression and prognosis of gastric cancer (GC) and the underlying mechanisms are still poorly understood. Here, we aimed at investigating clinicopathological significance of Ezh2 in GC and the mechanisms underlying its function in GC development. METHODS: The expression level of Ezh2 was determined by qRT-PCR, immunoblot, and immunohistochemistry analysis in 156 pairs of GC tissues and adjacent normal gastric mucosa tissues...
January 15, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29330295/epigenetic-reprogramming-of-pericentromeric-satellite-dna-in-premalignant-and-malignant-lesions
#12
Nadine H Brueckmann, Christina B Pedersen, Henrik J Ditzel, Morten F Gjerstorff
Repression of repetitive DNA is important for maintaining genomic stability, but is often perturbed in cancer. For instance, the megabase satellite domain at chromosome 1q12 is a common site of genetic rearrangements, such as translocations and deletions. Polycomb-group (PcG) proteins can be observed as large subnuclear domains called polycomb bodies, the composition and cellular function of which has remained elusive. This study, demonstrates that polycomb bodies are canonical subunits of the multiprotein polycomb repressive complex 1 (PRC1) deposited on 1q12 pericentromeric satellite DNA, which are normally maintained as constitutive heterochromatin by other mechanisms...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330200/pwwp-domain-interactor-of-polycombs11-interacts-with-polycomb-group-proteins-and-histones-and-regulates-arabidopsis-flowering-and-development
#13
Mareike L Hohenstatt, Pawel Mikulski, Olga Komarynets, Constanze Klose, Ina Kycia, Albert Jeltsch, Sara Farrona, Daniel Schubert
Polycomb-group (PcG) proteins mediate epigenetic gene regulation by setting H3K27me3 via Polycomb Repressive Complex 2 (PRC2). In plants, it is largely unclear how PcG proteins are recruited to their target genes. Here, we identified the PWWP-DOMAIN INTERACTOR OF POLYCOMBS1 (PWO1) protein, which interacts with all three Arabidopsis thaliana PRC2 histone methyltransferases and is required for maintaining full H3 occupancy at several Arabidopsis genes. PWO1 localizes and recruits CURLY LEAF to nuclear speckles in Nicotiana benthamiana nuclei, suggesting a role in spatial organization of PcG regulation...
January 12, 2018: Plant Cell
https://www.readbyqxmd.com/read/29327713/expression-of-enhancer-of-zeste-homolog-2-ezh2-protein-in-histiocytic-and-dendritic-cell-neoplasms-with-evidence-for-p-erk1-2-related-but-not-myc-or-p-stat3-related-cell-signaling
#14
Xuejun Tian, Jie Xu, Christopher Fletcher, Jason L Hornick, David M Dorfman
EZH2 is an important enzymatic subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2), which controls gene silencing through post-translational modification, and is overexpressed in various carcinomas and hematopoietic neoplasms. We found that the majority of cases of histiocytic and dendritic cell neoplasms, including histiocytic sarcoma, follicular dendritic cell sarcoma, Langerhans cell histiocytosis, and interdigitating dendritic cell sarcoma, show strong EZH2 expression by immunohistochemical staining, in contrast to benign histiocytic lesions and normal cellular counterparts, which did not show EZH2 expression, suggesting that this molecule may function as an oncogenic protein in these neoplasms...
January 12, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29323272/dominant-negative-smarca4-mutants-alter-the-accessibility-landscape-of-tissue-unrestricted-enhancers
#15
H Courtney Hodges, Benjamin Z Stanton, Katerina Cermakova, Chiung-Ying Chang, Erik L Miller, Jacob G Kirkland, Wai Lim Ku, Vaclav Veverka, Keji Zhao, Gerald R Crabtree
Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1...
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29323265/redox-dependent-bmi1-activity-drives-in-vivo-adult-cardiac-progenitor-cell-differentiation
#16
Diego Herrero, María Tomé, Susana Cañón, Francisco M Cruz, Rosa María Carmona, Encarna Fuster, Enrique Roche, Antonio Bernad
Accumulation of reactive oxygen species (ROS) is associated with several cardiovascular pathologies and with cell cycle exit by neonanatal cardiomyocytes, a key limiting factor in the regenerative capacity of the adult mammalian heart. The polycomb complex component BMI1 is linked to adult progenitors and is an important partner in DNA repair and redox regulation. We found that high BMI1 expression is associated with an adult Sca1+ cardiac progenitor sub-population with low ROS levels. In homeostasis, BMI1 repressed cell fate genes, including a cardiogenic differentiation program...
January 11, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29321178/transcription-factor-dependent-anti-repressive-mammalian-enhancers-exclude-h3k27me3-from-extended-genomic-domains
#17
Madhurima Saxena, Adrianna K San Roman, Nicholas K O'Neill, Rita Sulahian, Unmesh Jadhav, Ramesh A Shivdasani
Compacted chromatin and nucleosomes are known barriers to gene expression; the nature and relative importance of other transcriptional constraints remain unclear, especially at distant enhancers. Polycomb repressor complex 2 (PRC2) places the histone mark H3K27me3 predominantly at promoters, where its silencing activity is well documented. In adult tissues, enhancers lack H3K27me3, and it is unknown whether intergenic H3K27me3 deposits affect nearby genes. In primary intestinal villus cells, we identified hundreds of tissue-restricted enhancers that require the transcription factor (TF) CDX2 to prevent the incursion of H3K27me3 from adjoining areas of elevated basal marking into large well-demarcated genome domains...
January 10, 2018: Genes & Development
https://www.readbyqxmd.com/read/29320735/rybp-is-a-k63-ubiquitin-chain-binding-protein-that-inhibits-homologous-recombination-repair
#18
Mohammad A M Ali, Hilmar Strickfaden, Brian L Lee, Leo Spyracopoulos, Michael J Hendzel
Ring1-YY1-binding protein (RYBP) is a member of the non-canonical polycomb repressive complex 1 (PRC1), and like other PRC1 members, it is best described as a transcriptional regulator. However, several PRC1 members were recently shown to function in DNA repair. Here, we report that RYBP preferentially binds K63-ubiquitin chains via its Npl4 zinc finger (NZF) domain. Since K63-linked ubiquitin chains are assembled at DNA double-strand breaks (DSBs), we examined the contribution of RYBP to DSB repair. Surprisingly, we find that RYBP is K48 polyubiquitylated by RNF8 and rapidly removed from chromatin upon DNA damage by the VCP/p97 segregase...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29316023/sj%C3%A3-gren-s-syndrome-x-chromosome-dose-effect-an-epigenetic-perspective
#19
REVIEW
Jean-Luc C Mougeot, Braxton Noll, Farah K Bahrani Mougeot
Sjögren's syndrome (SS) is a chronic autoimmune disease affecting exocrine glands leading to mouth and eyes dryness. The extent to which epigenetic DNA methylation changes are responsible for an X-chromosome dose effect has yet to be determined. Our objectives were to (i) describe how epigenetic DNA methylation changes could explain an X-chromosome dose effect in SS for women with normal 46,XX genotype and (ii) determine the relevant relationships to this dose effect, between X-linked genes, genes controlling X-chromosome inactivation (XCI) and genes encoding associated transcription factors, all of which are differentially expressed and/or differentially methylated in the salivary glands of SS patients...
January 9, 2018: Oral Diseases
https://www.readbyqxmd.com/read/29314414/an-ortholog-of-curly-leaf-enhancer-of-zeste-like-1-is-required-for-proper-flowering-in-brachypodium-distachyon
#20
Aaron Lomax, Daniel P Woods, Yinxin Dong, Frédéric Bouché, Ying Rong, Kevin S Mayer, Xuehua Zhong, Richard M Amasino
Many plants require prolonged cold exposure to acquire the competence to flower. The process by which cold exposure results in competence is known as vernalization. In Arabidopsis thaliana, vernalization leads to the stable repression of the floral repressor FLOWERING LOCUS C via chromatin modification including an increase of trimethylation on lysine 27 of histone H3 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2). Vernalization in pooids is associated with the stable induction of a floral promoter, VERNALIZATION 1...
January 4, 2018: Plant Journal: for Cell and Molecular Biology
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