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https://www.readbyqxmd.com/read/27897169/ezh1-and-ezh2-promote-skeletal-growth-by-repressing-inhibitors-of-chondrocyte-proliferation-and-hypertrophy
#1
Julian C Lui, Presley Garrison, Quang Nguyen, Michal Ad, Chithra Keembiyehetty, Weiping Chen, Youn Hee Jee, Ellie Landman, Ola Nilsson, Kevin M Barnes, Jeffrey Baron
Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised...
November 29, 2016: Nature Communications
https://www.readbyqxmd.com/read/27862226/histone-h4-methyltransferase-suv420h2-maintains-fidelity-of-osteoblast-differentiation
#2
Khani Farzaneh, Roman Thaler, Christopher R Paradise, David R Deyle, Marianne Kruijthof-de Julio, Mario Galindo, Jonathan A Gordon, Gary S Stein, Amel Dudakovic, Andre J van Wijnen
Osteogenic lineage commitment and progression is controlled by multiple signaling pathways (e.g., WNT, BMP, FGF) that converge on bone-related transcription factors. Access of osteogenic transcription factors to chromatin is controlled by epigenetic regulators that generate post-translational modifications of histones ("histone code"), as well as read, edit and/or erase these modifications. Our understanding of the biological role of epigenetic regulators in osteoblast differentiation remains limited. Therefore, we performed next-generation RNA sequencing (RNA-seq) and established which chromatin-related proteins are robustly expressed in mouse bone tissues (e...
November 9, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27823969/targeting-ezh1-and-ezh2-contributes-to-the-suppression-of-fibrosis-associated-genes-by-mir-214-3p-in-cardiac-myofibroblasts
#3
Wen-Si Zhu, Chun-Mei Tang, Zhen Xiao, Jie-Ning Zhu, Qiu-Xiong Lin, Yong-Heng Fu, Zhi-Qin Hu, Zhuo Zhang, Min Yang, Xi-Long Zheng, Shu-Lin Wu, Zhi-Xin Shan
The role of microRNA-214-3p (miR-214-3p) in cardiac fibrosis was not well illustrated. The present study aimed to investigate the expression and potential target of miR-214-3p in angiotensin II (Ang-II)-induced cardiac fibrosis. MiR-214-3p was markedly decreased in the fibrotic myocardium of a mouse Ang-II infusion model, but was upregulated in Ang-II-treated mouse myofibroblasts. Cardiac fibrosis was shown attenuated in Ang-II-infused mice received tail vein injection of miR-214-3p agomir. Consistently, miR-214-3p inhibited the expression of Col1a1 and Col3a1 in mouse myofibroblasts in vitro...
November 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/27694924/impact-of-combinatorial-dysfunctions-of-tet2-and-ezh2-on-the-epigenome-in-the-pathogenesis-of-myelodysplastic-syndrome
#4
N Hasegawa, M Oshima, G Sashida, H Matsui, S Koide, A Saraya, C Wang, T Muto, K Takane, A Kaneda, K Shimoda, C Nakaseko, K Yokote, A Iwama
Somatic inactivating mutations in epigenetic regulators are frequently found in combination in myelodysplastic syndrome (MDS). However, the mechanisms by which combinatory mutations in epigenetic regulators promote the development of MDS remain unknown. Here we performed epigenomic profiling of hematopoietic progenitors in MDS mice hypomorphic for Tet2 following the loss of the polycomb-group gene Ezh2 (Tet2(KD/KD)Ezh2(Δ/Δ)). Aberrant DNA methylation propagated in a sequential manner from a Tet2-insufficient state to advanced MDS with deletion of Ezh2...
October 21, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27634302/dynamic-protein-interactions-of-the-polycomb-repressive-complex-2-during-differentiation-of-pluripotent-cells
#5
Giorgio Oliviero, Gerard L Brien, Ariane Waston, 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...
November 2016: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/27630126/chronic-myelogenous-leukemia-initiating-cells-require-polycomb-group-protein-ezh2
#6
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 (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) 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 and required for colony formation and survival and cell-cycle progression of CML cell lines...
November 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27468126/structure-activity-relationship-studies-for-enhancer-of-zeste-homologue-2-ezh2-and-enhancer-of-zeste-homologue-1-ezh1-inhibitors
#7
Xiaobao Yang, Fengling Li, Kyle D Konze, Jamel Meslamani, Anqi Ma, Peter J Brown, Ming-Ming Zhou, Cheryl H Arrowsmith, H Ümit Kaniskan, Masoud Vedadi, Jian Jin
EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias...
August 25, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27311868/aberrant-differential-expression-of-ezh1-and-ezh2-in-polycomb-repressive-complex-2-among-b-and-t-nk-cell-neoplasms
#8
Lamia Abdalkader, Takashi Oka, Katsuyoshi Takata, Hiaki Sato, Ichiro Murakami, Arie P Otte, Tadashi Yoshino
The Polycomb repressive complex-2 members (EZH2, EED, SUZ12 and EZH1) are important regulators of haematopoiesis, cell cycle and differentiation. Over-expression of EZH2 has been linked to cancer metastases and poor prognosis. Detailed information on the expression of other members in normal and neoplastic lymphoid tissue remains to be elucidated. Immunohistochemical and immunofluorescent analyses of 156 samples from haematopoietic neoplasms patients and 27 haematopoietic cell lines were used. B-cell neoplasms showed a significant over-expression of EZH2, EED and SUZ12 in the aggressive subtypes compared to the indolent subtypes and normal tissue (p = 0...
August 2016: Pathology
https://www.readbyqxmd.com/read/27216774/polycomb-prc2-complex-mediates-epigenetic-silencing-of-a-critical-osteogenic-master-regulator-in-the-hippocampus
#9
Rodrigo Aguilar, Fernando J Bustos, Mauricio Saez, Adriana Rojas, Miguel L Allende, Andre J van Wijnen, Brigitte van Zundert, Martin Montecino
During hippocampal neuron differentiation, the expression of critical inducers of non-neuronal cell lineages must be efficiently silenced. Runx2 transcription factor is the master regulator of mesenchymal cells responsible for intramembranous osteoblast differentiation and formation of the craniofacial bone tissue that surrounds and protects the central nervous system (CNS) in mammalian embryos. The molecular mechanisms that mediate silencing of the Runx2 gene and its downstream target osteogenic-related genes in neuronal cells have not been explored...
August 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27135271/no-significant-cytotoxic-effect-of-the-ezh2-inhibitor-tazemetostat-epz-6438-on-pediatric-glioma-cells-with-wildtype-histone-3-or-mutated-histone-3-3
#10
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
https://www.readbyqxmd.com/read/26774799/osteogenic-potential-of-human-adipose-tissue-derived-mesenchymal-stromal-cells-cultured-on-3d-printed-porous-structured-titanium
#11
Eric A Lewallen, Dakota L Jones, Amel Dudakovic, Roman Thaler, Christopher R Paradise, Hilal M Kremers, Matthew P Abdel, Sanjeev Kakar, Allan B Dietz, Robert C Cohen, David G Lewallen, Andre J van Wijnen
Integration of porous metal prosthetics, which restore form and function of irreversibly damaged joints, into remaining healthy bone is critical for implant success. We investigated the biological properties of adipose-tissue-derived mesenchymal stromal/stem cells (AMSCs) and addressed their potential to alter the in vitro microenvironment of implants. We employed human AMSCs as a practical source for musculoskeletal applications because these cells can be obtained in large quantities, are multipotent, and have trophic paracrine functions...
May 1, 2016: Gene
https://www.readbyqxmd.com/read/26427469/regulation-of-retinal-development-via-the-epigenetic-modification-of-histone-h3
#12
Sumiko Watanabe, Akira Murakami
We are interested in the roles of epigenetic mechanisms in retinal development. By ChIP-qPCR using whole retinal extracts at various developmental stages, we found that the levels of methylation of histones H3K27 and H3K4 and acetylation of histone H3 at specific loci in various genes, which play critical roles in retinal proliferation and differentiation, changed dramatically during retinal development. We next focused on the roles of H3K27 trimethylation in retinal development. Ezh1 and Ezh2 are methyltransferases that act on H3K27, while Jmjd3 and Utx are demethylases...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/26250110/loss-of-ezh2-results-in-precocious-mammary-gland-development-and-activation-of-stat5-dependent-genes
#13
Kyung Hyun Yoo, Sumin Oh, Keunsoo Kang, Tim Hensel, Gertraud W Robinson, Lothar Hennighausen
Establishment and differentiation of mammary alveoli during pregnancy are controlled by prolactin through the transcription factors STAT5A and STAT5B (STAT5), which also regulate temporal activation of mammary signature genes. This study addressed the question whether the methyltransferase and transcriptional co-activator EZH2 controls the differentiation clock of mammary epithelium. Ablation of Ezh2 from mammary stem cells resulted in precocious differentiation of alveolar epithelium during pregnancy and the activation of mammary-specific STAT5 target genes...
October 15, 2015: Nucleic Acids Research
https://www.readbyqxmd.com/read/26219303/ezh2-loss-in-hematopoietic-stem-cells-predisposes-mice-to-develop-heterogeneous-malignancies-in-an-ezh1-dependent-manner
#14
Makiko Mochizuki-Kashio, Kazumasa Aoyama, Goro Sashida, Motohiko Oshima, Takahisa Tomioka, Tomoya Muto, Changshan Wang, Atsushi Iwama
Recent genome sequencing revealed inactivating mutations in EZH2, which encodes an enzymatic component of polycomb-repressive complex 2 (PRC2), in patients with myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and MDS/MPN overlap disorders. We herein demonstrated that the hematopoietic-specific deletion of Ezh2 in mice induced heterogeneous hematopoietic malignancies. Myelodysplasia was detected in mice following the deletion of Ezh2, and resulted in the development of MDS and MDS/MPN. Thrombocytosis was induced by Ezh2 loss and sustained in some mice with myelodysplasia...
September 3, 2015: Blood
https://www.readbyqxmd.com/read/26118502/inactivation-of-eed-impedes-mll-af9-mediated-leukemogenesis-through-cdkn2a-dependent-and-cdkn2a-independent-mechanisms-in-a-murine-model
#15
Etienne Danis, Taylor Yamauchi, Kristen Echanique, Jessica Haladyna, Roshni Kalkur, Simone Riedel, Nan Zhu, Huafeng Xie, Kathrin M Bernt, Stuart H Orkin, Scott A Armstrong, Tobias Neff
Polycomb repressive complex 2 (PRC2) is a chromatin regulator with central roles in development and cancer. The canonical function of PRC2 is the trimethylation of histone 3 on lysine residue 27. This epigenetic modification is associated with gene silencing. Both tumor suppressor and oncogenic functions have been reported for PRC2, depending on cellular context. In leukemia mediated by the leukemogenic fusion MLL-AF9, complete ablation of canonical PRC2 function by genetic inactivation of the core component embryonic ectoderm development (Eed) or by combined pharmacologic inhibition of the PRC2 methyltransferases EZH2 and EZH1 has a strong anti-leukemic effect, and this effect has been linked to de-repression of the PRC2 target locus Cdkn2a...
November 2015: Experimental Hematology
https://www.readbyqxmd.com/read/26041287/h3k27-demethylation-at-the-proviral-promoter-sensitizes-latent-hiv-to-the-effects-of-vorinostat-in-ex-vivo-cultures-of-resting-cd4-t-cells
#16
Manoj K Tripathy, Mary E M McManamy, Brandon D Burch, Nancie M Archin, David M Margolis
UNLABELLED: Histone methyltransferase inhibitors (HMTis) and histone deacetylase inhibitors (HDACis) are reported to synergistically induce the expression of latent human immunodeficiency virus type 1 (HIV-1), but studies have largely been performed with cell lines. As specific and potent HMTis directed at EZH1 (enhancer of zeste 2 Polycomb repressive complex 2 subunit 1)/EZH2 are now in human testing, we wished to rigorously test such an inhibitor in a primary resting T-cell model of HIV latency...
August 2015: Journal of Virology
https://www.readbyqxmd.com/read/26036803/polycomb-repressive-complex-2-component-suz12-is-required-for-hematopoietic-stem-cell-function-and-lymphopoiesis
#17
Stanley C W Lee, Sarah Miller, Craig Hyland, Maria Kauppi, Marion Lebois, Ladina Di Rago, Donald Metcalf, Sarah A Kinkel, Emma C Josefsson, Marnie E Blewitt, Ian J Majewski, Warren S Alexander
Polycomb repressive complex 2 (PRC2) is a chromatin modifier that regulates stem cells in embryonic and adult tissues. Loss-of-function studies of PRC2 components have been complicated by early embryonic dependence on PRC2 activity and the partial functional redundancy of enhancer of zeste homolog 1 (Ezh1) and enhancer of zeste homolog 2 (Ezh2), which encode the enzymatic component of PRC2. Here, we investigated the role of PRC2 in hematopoiesis by conditional deletion of suppressor of zeste 12 protein homolog (Suz12), a core component of PRC2...
July 9, 2015: Blood
https://www.readbyqxmd.com/read/26027790/targeting-ezh2-and-prc2-dependence-as-novel-anticancer-therapy
#18
REVIEW
Bowen Xu, Kyle D Konze, Jian Jin, Gang Greg Wang
Distinctive patterns of chromatin modification control gene expression and define cellular identity during development and cell differentiation. Polycomb repressive complex 2 (PRC2), the sole mammalian enzymatic complex capable of establishing gene-repressive high-degree methylation of histone H3 at lysine 27 (H3K27), plays crucial roles in regulation of normal and malignant hematopoiesis. Recently, increasing evidence has indicated that recurrent gain-of-function mutation and overexpression of EZH2, the catalytic subunit of PRC2, drive and promote malignant transformation such as B-cell lymphomagenesis, providing a rationale for PRC2 inhibition as a novel anticancer strategy...
August 2015: Experimental Hematology
https://www.readbyqxmd.com/read/25938557/confluence-induced-squamous-differentiation-is-not-accompanied-by-changes-in-h3k27me3-repressive-epigenetic-mark
#19
Orla M Gannon, Lilia Merida de Long, Mehlika Hazar-Rethinam, Eleni Topkas, Liliana B Endo-Munoz, Gethin P Thomas, Ping Zhang, Nicholas A Saunders
Recent studies have reported that epigenetic mechanisms may regulate the initiation and progress of squamous differentiation in normal and transformed keratinocytes. In particular, the role of the repressive H3K27me3 mark in the regulation of squamous differentiation has been prominent. However, there is conflicting literature showing that squamous differentiation may be dependent upon or independent of changes in H3K27me3 status. In this study we have examined the binding of trimethylated H3K27 to the promoters of proliferation or differentiation genes in keratinocytes undergoing squamous differentiation in vitro and in vivo...
October 2015: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/25806020/transcriptional-response-of-polycomb-group-genes-to-status-epilepticus-in-mice-is-modified-by-prior-exposure-to-epileptic-preconditioning
#20
James P Reynolds, Suzanne F C Miller-Delaney, Eva M Jimenez-Mateos, Takanori Sano, Ross C McKiernan, Roger P Simon, David C Henshall
Exposure of the brain to brief, non-harmful seizures can activate protective mechanisms that temporarily generate a damage-refractory state. This process, termed epileptic tolerance, is associated with large-scale down-regulation of gene expression. Polycomb group (PcG) proteins are master controllers of gene silencing during development that are re-activated by injury to the brain. Here, we explored the transcriptional response of genes associated with polycomb repressive complex (PRC) 1 (Ring1A, Ring1B, and Bmi1) and PRC2 (Ezh1, Ezh2, and Suz12), as well as additional transcriptional regulators Sirt1, Yy1, and Yy2, in a mouse model of status epilepticus (SE)...
2015: Frontiers in Neurology
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