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https://www.readbyqxmd.com/read/27927750/mdm2-as-a-chromatin-modifier
#1
REVIEW
Magdalena Wienken, Ute M Moll, Matthias Dobbelstein
Mdm2 is the key negative regulator of the tumour suppressor p53, making it an attractive target for anti-cancer drug design. We recently identified a new role of Mdm2 in gene repression through its direct interaction with several proteins of the polycomb group (PcG) family. PcG proteins form polycomb repressive complexes PRC1 and PRC2. PRC2 (via EZH2) mediates histone 3 lysine 27 (H3K27) trimethylation, and PRC1 (via RING1B) mediates histone 2A lysine 119 (H2AK119) monoubiquitination. Both PRCs mostly support a compact and transcriptionally silent chromatin structure...
November 9, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27926872/deletion-of-the-polycomb-group-protein-ezh2-leads-to-compromised-self-renewal-and-differentiation-defects-in-human-embryonic-stem-cells
#2
Adam Collinson, Amanda J Collier, Natasha P Morgan, Arnold R Sienerth, Tamir Chandra, Simon Andrews, Peter J Rugg-Gunn
Through the histone methyltransferase EZH2, the Polycomb complex PRC2 mediates H3K27me3 and is associated with transcriptional repression. PRC2 regulates cell-fate decisions in model organisms; however, its role in regulating cell differentiation during human embryogenesis is unknown. Here, we report the characterization of EZH2-deficient human embryonic stem cells (hESCs). H3K27me3 was lost upon EZH2 deletion, identifying an essential requirement for EZH2 in methylating H3K27 in hESCs, in contrast to its non-essential role in mouse ESCs...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27926531/an-annotated-list-of-bivalent-chromatin-regions-in-human-es-cells-a-new-tool-for-cancer-epigenetic-research
#3
Franck Court, Philippe Arnaud
CpG islands (CGI) marked by bivalent chromatin in stem cells are believed to be more prone to aberrant DNA methylation in tumor cells. The robustness and genome-wide extent of this instructive program in different cancer types remain to be determined. To address this issue we developed a user-friendly approach to integrate the stem cell chromatin signature in customized DNA methylation analyses. We used publicly available ChIP-sequencing datasets of several human embryonic stem cell (hESC) lines to determine the extent of bivalent chromatin genome-wide...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27923618/novel-3-methylindoline-inhibitors-of-ezh2-design-synthesis-and-sar
#4
Amantullah Ansari, Sharad Satalkar, Varshavekumar Patil, Amit S Shete, Simranjeet Kaur, Ashu Gupta, Siddhartha Singh, Mohd Raja, Daniel L Severance, Sebastián Bernales, Sarvajit Chakravarty, David T Hung, Son M Pham, Francisco J Herrera, Roopa Rai
EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core...
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27920939/epigenetic-mechanisms-drive-the-progression-of-neurofibromas-to-malignant-peripheral-nerve-sheath-tumors
#5
REVIEW
Krish Suresh, Tamara Kliot, Andrea Piunti, Michel Kliot
THINKING OUTSIDE THE BOX: The polycomb repressive complex 2 (PRC2) is a histone methyltransferase complex known to repress gene expression. There is a large body of experimental evidence that supports its role in promoting tumorigenicity by suppressing tumor suppressor genes. Here, we discuss the surprising findings that, in neurofibromas, it may have a completely different role as a tumor suppressor; mutations of PRC2 lead to conversion of benign neurofibromas into malignant peripheral nerve sheath tumors (MPNSTs) by de-repressing and thereby activating genes driving cell growth and development...
2016: Surgical Neurology International
https://www.readbyqxmd.com/read/27902735/role-of-hepatic-specific-transcription-factors-and-polycomb-repressive-complex-2-during-induction-of-fibroblasts-to-hepatic-fate
#6
Shima Rastegar-Pouyani, Niusha Khazaei, Ping Wee, Abdulshakour Mohammadnia, Moein Yaqubi
Direct reprogramming using defined sets of transcription factors (TFs) is a recent strategy for generating induced hepatocytes (iHeps) from fibroblasts for use in regenerative medicine and drug development. Comprehensive studies detailing the regulatory role of TFs during this reprogramming process could help increase its efficiency. This study aimed to find the TFs with the greatest influences on the generation of iHeps from fibroblasts, and to further understand their roles in the regulation of the gene expression program...
2016: PloS One
https://www.readbyqxmd.com/read/27898079/a-dna-element-that-remembers-winter
#7
Chenlong Li, Yuhai Cui
Polycomb-mediated silencing of the floral repressor gene FLC in response to long-term cold is a central event during vernalization in Arabidopsis thaliana, but how it is initiated is unclear. Two new studies identify a DNA element that mediates FLC silencing by attracting a pair of transcriptional repressors, VAL1 and VAL2, which in turn trigger epigenetic silencing by the Polycomb complex PHD-PRC2.
November 29, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27892467/jarid2-binds-mono-ubiquitylated-h2a-lysine-119-to-mediate-crosstalk-between-polycomb-complexes-prc1-and-prc2
#8
Sarah Cooper, Anne Grijzenhout, Elizabeth Underwood, Katia Ancelin, Tianyi Zhang, Tatyana B Nesterova, Burcu Anil-Kirmizitas, Andrew Bassett, Susanne M Kooistra, Karl Agger, Kristian Helin, Edith Heard, Neil Brockdorff
The Polycomb repressive complexes PRC1 and PRC2 play a central role in developmental gene regulation in multicellular organisms. PRC1 and PRC2 modify chromatin by catalysing histone H2A lysine 119 ubiquitylation (H2AK119u1), and H3 lysine 27 methylation (H3K27me3), respectively. Reciprocal crosstalk between these modifications is critical for the formation of stable Polycomb domains at target gene loci. While the molecular mechanism for recognition of H3K27me3 by PRC1 is well defined, the interaction of PRC2 with H2AK119u1 is poorly understood...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27886392/deregulated-expression-of-ezh2-in-congenital-brainstem-disconnection
#9
P G Barth, E Aronica, S Fox, K Fluiter, M A J Weterman, A Poretti, D C Miller, E Boltshauser, B Harding, M Santi, F Baas
Congenital brainstem disconnection (CBSD) is an enigmatic embryo-fetal defect presenting as (sub)total absence of a segment between mesencephalon and lower brainstem. Rostro-caudal limits of the defect vary while the basal pons is always involved and the cerebellum is globally hypoplastic. A recent update and review[1] lists 14 cases, including 3 brain autopsy studies[1-3]. Necrosis and glial- or inflammatory reactions were absent. Inferior olivary nuclei were small or absent, pontine nuclei depleted, and the cerebellar dentate nuclei dysplastic...
November 25, 2016: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/27863226/epop-interacts-with-elongin-bc-and-usp7-to-modulate-the-chromatin-landscape
#10
Robert Liefke, Violetta Karwacki-Neisius, Yang Shi
Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs), the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core, and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions, and its mis-regulation is linked to cancer development. Here, we show that, in mESCs, the Polycomb repressive complex 2 (PRC2)-associated protein EPOP (Elongin BC and Polycomb Repressive Complex 2-associated protein; a...
November 17, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27863225/epop-functionally-links-elongin-and-polycomb-in-pluripotent-stem-cells
#11
Malte Beringer, Paola Pisano, Valerio Di Carlo, Enrique Blanco, Paul Chammas, Pedro Vizán, Arantxa Gutiérrez, Sergi Aranda, Bernhard Payer, Michael Wierer, Luciano Di Croce
The cellular plasticity of pluripotent stem cells is thought to be sustained by genomic regions that display both active and repressive chromatin properties. These regions exhibit low levels of gene expression, yet the mechanisms controlling these levels remain unknown. Here, we describe Elongin BC as a binding factor at the promoters of bivalent sites. Biochemical and genome-wide analyses show that Elongin BC is associated with Polycomb Repressive Complex 2 (PRC2) in pluripotent stem cells. Elongin BC is recruited to chromatin by the PRC2-associated factor EPOP (Elongin BC and Polycomb Repressive Complex 2 Associated Protein, also termed C17orf96, esPRC2p48, E130012A19Rik), a protein expressed in the inner cell mass of the mouse blastocyst...
November 17, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27856763/normal-chromosome-conformation-depends-on-subtelomeric-facultative-heterochromatin-in-neurospora-crassa
#12
Andrew D Klocko, Tereza Ormsby, Jonathan M Galazka, Neena A Leggett, Miki Uesaka, Shinji Honda, Michael Freitag, Eric U Selker
High-throughput chromosome conformation capture (Hi-C) analyses revealed that the 3D structure of the Neurospora crassa genome is dominated by intra- and interchromosomal links between regions of heterochromatin, especially constitutive heterochromatin. Elimination of trimethylation of lysine 9 on histone H3 (H3K9me3) or its binding partner Heterochromatin Protein 1 (HP1)-both prominent features of constitutive heterochromatin-have little effect on the Hi-C pattern. It remained possible that di- or trimethylation of lysine 27 on histone H3 (H3K27me2/3), which becomes localized in regions of constitutive heterochromatin when H3K9me3 or HP1 are lost, plays a critical role in the 3D structure of the genome...
November 16, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27852821/meg3-long-noncoding-rna-contributes-to-the-epigenetic-regulation-of-epithelial-mesenchymal-transition-in-lung-cancer-cell-lines
#13
Minoru Terashima, Shoichiro Tange, Akihiko Ishimura, Takeshi Suzuki
Histone methylation is implicated in a number of biological and pathological processes including cancer development. In this study, we investigated the molecular mechanism for the recruitment of Polycomb repressive complex-2 (PRC2) and its accessory component, JARID2, to chromatin, which regulates methylation of lysine 27 of histone H3 (H3K27), during epithelial-mesenchymal transition (EMT) of cancer cells. The expression of MEG3 long noncoding RNA (lncRNA), which could interact with JARID2, was clearly increased during Transforming Growth Factor-beta (TGF-β)-induced EMT of human lung cancer cell lines...
November 16, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27845897/the-jazf1-suz12-fusion-protein-disrupts-prc2-complexes-and-impairs-chromatin-repression-during-human-endometrial-stromal-tumorogenesis
#14
Xianyong Ma, Jinglan Wang, Jianhui Wang, Charles X Ma, Xiaobin Gao, Vytas Patriub, Jeffrey L Sklar
The Polycomb repressive complex 2 (PRC2), which contains three core proteins EZH2, EED and SUZ12, controls chromatin compaction and transcription repression through trimethylation of lysine 27 on histone 3. The (7;17)(p15;q21) chromosomal translocation present in most cases of endometrial stromal sarcomas (ESSs) results in the in-frame fusion of the JAZF1 and SUZ12 genes. We have investigated whether and how the fusion protein JAZF1-SUZ12 functionally alters PRC2. We found that the fusion protein exists at high levels in ESS containing the t(7;17)...
November 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27845772/long-intergenic-noncoding-rna-00511-acts-as-an-oncogene-in-non-small-cell-lung-cancer-by-binding-to-ezh2-and-suppressing-p57
#15
Cheng-Cao Sun, Shu-Jun Li, Guang Li, Rui-Xi Hua, Xu-Hong Zhou, De-Jia Li
Long noncoding RNAs (lncRNAs) play crucial roles in carcinogenesis. However, the function and mechanism of lncRNAs in human non-small-cell lung cancer (NSCLC) are still remaining largely unknown. Long intergenic noncoding RNA 00511 (LINC00511) has been found to be upregulated and acts as an oncogene in breast cancer, but little is known about its expression pattern, biological function and underlying mechanism in NSCLC. Herein, we identified LINC00511 as an oncogenic lncRNA by driving tumorigenesis in NSCLC...
November 15, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27830540/multifaceted-role-of-the-polycomb-group-gene-ezh2-in-hematological-malignancies
#16
REVIEW
Goro Sashida, Atsushi Iwama
Polycomb repressive complex (PRC) is a critical regulator of normal tissue homeostasis as well as tumorigenesis. EZH2, an enzymatic subunit of PRC2, is a histone H3K27 methyltransferase that functions in the regulation of gene silencing. EZH2 overexpression was first identified in prostate and breast cancers and is associated with poor clinical outcome. Subsequently, gain- and loss-of-function mutations of EZH2 have been identified in various tumors, including hematological malignancies, implicating EZH2 as either an oncogene or a tumor suppressor gene, depending on the cancer type...
November 9, 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27818691/osteogenic-differentiation-of-human-amniotic-fluid-mesenchymal-stem-cells-is-determined-by-epigenetic-changes
#17
Monika Glemžaitė, Rūta Navakauskienė
Osteogenic differentiation of human amniotic fluid derived mesenchymal stem cells (AF-MSCs) has been widely studied in vitro and in vivo as a potential tool for regenerative medicine and tissue engineering. While most of the studies analyze changes in transcriptional profile during differentiation to date there is not much information regarding epigenetic changes in AF-MSCs during differentiation. The aim of our study was to evaluate epigenetic changes during osteogenic differentiation of AF-MS cells. Isolated AF-MSCs were characterized morphologically and osteogenic differentiation was confirmed by cell staining and determining expression of alkaline phosphatase and osteopontin by RT-qPCR...
2016: Stem Cells International
https://www.readbyqxmd.com/read/27811080/fie-a-nuclear-prc2-protein-forms-cytoplasmic-complexes-in-arabidopsis-thaliana
#18
Moran Oliva, Yana Butenko, Tzung-Fu Hsieh, Ofir Hakim, Aviva Katz, Nechama I Smorodinsky, Daphna Michaeli, Robert L Fischer, Nir Ohad
Polycomb group (PcG) proteins are evolutionarily conserved chromatin modifiers that regulate developmental pathways in plants. PcGs form nuclear multi-subunit Polycomb Repressive Complexes (PRCs). The PRC2 complex mediates gene repression via methylation of lysine 27 on histone H3, which consequently leads to chromatin condensation. In Arabidopsis thaliana, several PRC2 complexes with different compositions were identified, each controlling a particular developmental program.The core subunit FIE is crucial for PRC2 function throughout the plant life cycle, yet accurate information on its spatial and temporal localization was absent...
November 2016: Journal of Experimental Botany
https://www.readbyqxmd.com/read/27803189/regulation-of-vegetative-phase-change-by-swi2-snf2-chromatin-remodeling-atpase-brahma
#19
Yunmin Xu, Changkui Guo, Bingying Zhou, Chenlong Li, Huasen Wang, Ben Zheng, Han Ding, Zhujun Zhu, Angela Peragine, Yuhai Cui, Scott Poethig, Gang Wu
Plants progress from a juvenile vegetative phase of development to an adult vegetative phase of development before they enter the reproductive phase. miR156 has been shown to be the master regulator of the juvenile-to-adult transition in plants. However, the mechanism of how miR156 is transcriptionally regulated still remains elusive. In a forward genetic screen, we identified that a mutation in the SWI2/SNF2 chromatin remodeling ATPase BRAHMA (BRM) exhibited an accelerated vegetative phase change phenotype by reducing the expression of miR156, which in turn caused a corresponding increase in the levels of SQUAMOSA PROMOTER BINDING PROTEIN LIKE genes...
December 2016: Plant Physiology
https://www.readbyqxmd.com/read/27793053/epigenetic-regulation-of-cancer-biology-and-anti-tumor-immunity-by-ezh2
#20
Anthos Christofides, Theodoros Karantanos, Kankana Bardhan, Vassiliki A Boussiotis
Polycomb group proteins regulate chromatin structure and have an important regulatory role on gene expression in various cell types. Two polycomb group complexes (Polycomb repressive complex 1 (PRC1) and 2 (PRC2)) have been identified in mammalian cells. Both PRC1 and PRC2 compact chromatin, and also catalyze histone modifications. PRC1 mediates monoubiquitination of histone H2A, whereas PRC2 catalyzes methylation of histone H3 on lysine 27. These alterations of histones can lead to altered gene expression patterns by regulating chromatin structure...
October 26, 2016: Oncotarget
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