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Judit Symmank, Cathrin Bayer, Christiane Schmidt, Anne Hahn, Daniel Pensold, Geraldine Zimmer
Epigenetic mechanisms of gene regulation, including DNA methylation and histone modifications, call increasing attention in the context of development and human health. Thereby, interactions between DNA methylating enzymes and histone modifications tremendously multiply the spectrum of potential regulatory functions. Epigenetic networks are critically involved in the establishment and functionality of neuronal circuits that are composed of gamma-aminobutyric acid (GABA)-positive inhibitory interneurons and excitatory principal neurons in the cerebral cortex...
June 18, 2018: Epigenetics: Official Journal of the DNA Methylation Society
Kristian W Pajtler, Ji Wen, Martin Sill, Tong Lin, Wilda Orisme, Bo Tang, Jens-Martin Hübner, Vijay Ramaswamy, Sujuan Jia, James D Dalton, Kelly Haupfear, Hazel A Rogers, Chandanamali Punchihewa, Ryan Lee, John Easton, Gang Wu, Timothy A Ritzmann, Rebecca Chapman, Lukas Chavez, Fredrick A Boop, Paul Klimo, Noah D Sabin, Robert Ogg, Stephen C Mack, Brian D Freibaum, Hong Joo Kim, Hendrik Witt, David T W Jones, Baohan Vo, Amar Gajjar, Stan Pounds, Arzu Onar-Thomas, Martine F Roussel, Jinghui Zhang, J Paul Taylor, Thomas E Merchant, Richard Grundy, Ruth G Tatevossian, Michael D Taylor, Stefan M Pfister, Andrey Korshunov, Marcel Kool, David W Ellison
Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations...
June 16, 2018: Acta Neuropathologica
Ioanna Triviai, Silke Zeschke, Jan Rentel, Marios Spanakis, Theo Scherer, Razif Gabdoulline, Victoria Panagiota, Felicitas Thol, Michael Heuser, Carol Stocking, Nicolaus Kröger
Primary myelofibrosis (PMF) is a hematopoietic stem cell (HSC) disease, characterized by aberrant differentiation of all myeloid lineages and profound disruption of the bone marrow niche. PMF samples carry several mutations, but their cell origin and hierarchy in regulating the different waves of clonal and aberrant myeloproliferation from the prime HSC compartment is poorly understood. Genotyping of >2000 colonies from CD133+HSC and progenitors from PMF patients confirmed the complex genetic heterogeneity within the neoplastic population...
June 15, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Masakatsu Kageyama, Kejuan Li, Shuang Sun, Guoqing Xing, Ran Gao, Zhongfang Lei, Zhenya Zhang
Honey bee larvae products have been widely used as traditional daily supplements and complementary medicine for health promotion. However, there is little scientific evidence about their bioactivities. This study was designed to examine the anti-tumor and anti-metastasis effects of honey bee larvae powder (HLP) and explore the underlying mechanism. A subcutaneous transplantation model (murine breast cancer cell 4T1-LUC) and lung metastasis model (murine melanoma cell B16-F10) were established to evaluate the anti-tumor and anti-metastasis effects of HLP...
June 12, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Sangeeta Goswami, Irina Apostolou, Jan Zhang, Jill Skepner, Swetha Anandhan, Xuejun Zhang, Liangwen Xiong, Patrick Trojer, Ana Aparicio, Sumit K Subudhi, James P Allison, Hao Zhao, Padmanee Sharma
EZH2-mediated epigenetic regulation of T cell differentiation and regulatory T cell function has been described previously; however, the role of EZH2 in T cell-mediated anti-tumor immunity, especially in the context of immune checkpoint therapy, is not understood. Here, we showed that genetic depletion of EZH2 in regulatory T cells (FoxP3creEZH2fl/fl mice) leads to robust anti-tumor immunity. In addition, pharmacological inhibition of EZH2 in human T cells using CPI-1205 elicited phenotypic and functional alterations of the regulatory T cells and enhanced cytotoxic activity of effector T cells...
June 15, 2018: Journal of Clinical Investigation
Matthew Bratkowski, Xin Yang, Xin Liu
Polycomb repressive complex 2 (PRC2) mediates trimethylation of histone H3K27 (H3K27me3), an epigenetic hallmark for repressed chromatin. Overactive mutants of the histone lysine methyltransferase subunit of PRC2, Ezh2, are found in various types of cancers. Pyridone-containing inhibitors such as GSK126 compete with S-adenosylmethionine (SAM) for Ezh2 binding and effectively inhibit PRC2 activity. PRC2 from the thermophilic fungus Chaetomium thermophilum (ct) is functionally similar to the human version in several regards and has the added advantage of producing high-resolution crystal structures, although inhibitor-bound structures of human or human/chameleon PRC2 are also available at up to 2...
June 14, 2018: Scientific Reports
Yonglong Hong, Haitao He, Wen Sui, Jingge Zhang, Shenfu Zhang, Dajiang Yang
Following the publication of this article, we realize that the title appeared incorrectly: This appeared in print as "Long non‑coding RNA H1 promotes cell proliferation and invasion by acting as a ceRNA of miR‑138 and releasing EZH2 in oral squamous cell carcinoma", and the corrected title is now featured above ("H1" should have read as "H19"). Note that this error did not have any bearing on the results reported in the paper, or on the conclusions therein. We regret any inconvenience that this mistake has caused...
June 1, 2018: International Journal of Oncology
Amel Dudakovic, Emily Camilleri, Christopher R Paradise, Rebekah M Samsonraj, Martina Gluscevic, Carlo Alberto Paggi, Dana L Begun, Farzaneh Khani, Oksana Pichurin, Farah S Ahmed, Ranya Elsayed, Mohammed Elsalanty, Meghan E McGee-Lawrence, Marcel Karperien, Scott M Riester, Roman Thaler, Jennifer J Westendorf, Andre J van Wijnen
Epigenetic mechanisms control skeletal development and osteoblast differentiation. Pharmacological inhibition of the histone 3 Lys-27 (H3K27) methyltransferase enhancer of zeste homolog 2 (Ezh2) in wildtype mice enhances osteogenesis and stimulates bone formation. However, conditional genetic loss of Ezh2 early in the mesenchymal lineage (i.e. through excision via Prrx1 promoter-driven Cre) causes skeletal abnormalities due to patterning defects. Here, we addressed the key question whether Ezh2 controls osteoblastogenesis at later developmental stages beyond patterning...
June 13, 2018: Journal of Biological Chemistry
David Wang, Jason Quiros, Kelly Mahuron, Chien-Chun Pai, Valeria Ranzani, Arabella Young, Stephanie Silveria, Tory Harwin, Arbi Abnousian, Massimiliano Pagani, Michael D Rosenblum, Frederic Van Gool, Lawrence Fong, Jeffrey A Bluestone, Michel DuPage
Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors...
June 12, 2018: Cell Reports
Suowen Xu, Yanni Xu, Meimei Yin, Shuya Zhang, Peng Liu, Marina Koroleva, Shuyi Si, Peter J Little, Jaroslav Pelisek, Zheng Gen Jin
Rationale : Atherosclerosis is a chronic inflammatory and epigenetic disease that is influenced by different patterns of blood flow. However, the epigenetic mechanism whereby atheroprotective flow controls endothelial gene programming remains elusive. Here, we investigated the possibility that flow alters endothelial gene expression through epigenetic mechanisms. Methods : E n face staining and western blot were used to detect protein expression. Real-time PCR was used to determine relative gene expression...
2018: Theranostics
Andrew M Intlekofer, Erel Joffe, Connie L Batlevi, Patrick Hilden, Jie He, Venkatraman E Seshan, Andrew D Zelenetz, M Lia Palomba, Craig H Moskowitz, Carol Portlock, David J Straus, Ariela Noy, Steven M Horwitz, John F Gerecitano, Alison Moskowitz, Paul Hamlin, Matthew J Matasar, Anita Kumar, Marcel R van den Brink, Kristina M Knapp, Janine D Pichardo, Michelle K Nahas, Sally E Trabucco, Tariq Mughal, Amanda R Copeland, Elli Papaemmanuil, Mathai Moarii, Ross L Levine, Ahmet Dogan, Vincent A Miller, Anas Younes
We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma)...
June 12, 2018: Blood Cancer Journal
Daniel T Youmans, Jens C Schmidt, Thomas R Cech
Polycomb-repressive complex 2 (PRC2) is a histone methyltransferase that promotes epigenetic gene silencing, but the dynamics of its interactions with chromatin are largely unknown. Here we quantitatively measured the binding of PRC2 to chromatin in human cancer cells. Genome editing of a HaloTag into the endogenous EZH2 and SUZ12 loci and single-particle tracking revealed that ∼80% of PRC2 rapidly diffuses through the nucleus, while ∼20% is chromatin-bound. Short-term treatment with a small molecule inhibitor of the EED-H3K27me3 interaction had no immediate effect on the chromatin residence time of PRC2...
June 11, 2018: Genes & Development
Jianming Tang, Guansheng Zhong, Jianhui Wu, Haiyan Chen, Yongshi Jia
Increasing evidences have shown that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. However, the contributions of lncRNAs to colorectal cancer remain largely unknown. Here, we identify a lncRNA AFAP1-AS1 that facilitates colorectal cancer, where it is upregulated. AFAP1-AS1 expression was associated with colorectal cancer patient survival. AFAP1-AS1 knockdown inhibited cell proliferation, cell cycle, and tumorigenesis in an subcutaneous mouse xenograft model system. Further data demonstrated that AFAP1-AS1 was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of EZH2 target genes...
2018: American Journal of Cancer Research
Xiaofen Zhou, Erjie Xia, Adheesh Bhandari, Chen Zheng, Jingjing Xiang, Yaoyao Guan, Xiaohua Zhang
Dysregulation of cell proliferation and death is considered the foundation of the malignant biological characteristics of cancer. In this study, we conducted a comprehensive analysis of a massively parallel whole transcriptome resequencing of paired papillary thyroid cancer and normal thyroid tissues from 19 patients. In addition, we found that LRP4, a member of the low-density lipoprotein receptor-related protein family, is significantly overexpressed in thyroid carcinoma. We demonstrated through quantitative real-time polymerase chain reaction (qRT-PCR) that LRP4 is upregulated in papillary thyroid cancer (PTC) tissues...
June 7, 2018: Biochemical and Biophysical Research Communications
Abhishek A Singh, Francesca Petraglia, Angela Nebbioso, Guoqiang Yi, Mariarosaria Conte, Sergio Valente, Amit Mandoli, Lucia Scisciola, Rik Lindeboom, Hinri Kerstens, Eva M Janssen-Megens, Farzin Pourfarzad, Ehsan Habibi, Kim Berentsen, Bowon Kim, Colin Logie, Simon Heath, Albertus T J Wierenga, Laura Clarke, Paul Flicek, Joop H Jansen, Taco Kuijpers, Marie Laure Yaspo, Veronique Della Valle, Olivier Bernard, Ivo Gut, Edo Vellenga, Hendrik G Stunnenberg, Antonello Mai, Lucia Altucci, Joost H A Martens
Epigenomic alterations have been associated with both pathogenesis and progression of cancer. Here, we analyzed the epigenome of two high-risk APL (hrAPL) patients and compared it to non-high-risk APL cases. Despite the lack of common genetic signatures, we found that human hrAPL blasts from patients with extremely poor prognosis display specific patterns of histone H3 acetylation, specifically hyperacetylation at a common set of enhancer regions. In addition, unique profiles of the repressive marks H3K27me3 and DNA methylation were exposed in high-risk APLs...
May 22, 2018: Oncotarget
Francesca Petraglia, Abhishek A Singh, Vincenzo Carafa, Angela Nebbioso, Mariarosaria Conte, Lucia Scisciola, Sergio Valente, Alfonso Baldi, Amit Mandoli, Valeria Belsito Petrizzi, Concetta Ingenito, Sandro De Falco, Valeria Cicatiello, Ivana Apicella, Eva M Janssen-Megens, Bowon Kim, Guoqiang Yi, Colin Logie, Simon Heath, Menotti Ruvo, Albertus T J Wierenga, Paul Flicek, Marie Laure Yaspo, Veronique Della Valle, Olivier Bernard, Stefano Tomassi, Ettore Novellino, Alessandra Feoli, Gianluca Sbardella, Ivo Gut, Edo Vellenga, Hendrik G Stunnenberg, Antonello Mai, Joost H A Martens, Lucia Altucci
Epigenetic alterations have been associated with both pathogenesis and progression of cancer. By screening of library compounds, we identified a novel hybrid epi-drug MC2884, a HAT/EZH2 inhibitor, able to induce bona fide cancer-selective cell death in both solid and hematological cancers in vitro , ex vivo and in vivo xenograft models. Anticancer action was due to an epigenome modulation by H3K27me3, H3K27ac, H3K9/14ac decrease, and to caspase-dependent apoptosis induction. MC2884 triggered mitochondrial pathway apoptosis by up-regulation of cleaved-BID, and strong down-regulation of BCL2...
May 22, 2018: Oncotarget
Yong-Yan Bi, Gang Shen, Yong Quan, Wei Jiang, Fulin Xu
Gliomas are the commonest and most aggressive primary malignant tumor in the central nervous system. Long noncoding RNAs (lncRNAs) have been identified to act as crucial regulators in multiple biological processes, including tumorigenesis. FAM83H antisense RNA1 (FAM83H-AS1) has been uncovered to be dysregulated in several cancers. However, the biological role of FAM83H-AS1 in glioma still needs to be investigated. Currently, our findings indicated that FAM83H-AS1 was upregulated in glioma tissues and cell lines and high level of FAM83H-AS1 was associated with poor prognosis of glioma...
June 5, 2018: Journal of Cellular Physiology
Indrabahadur Singh, Adriana Contreras, Julio Cordero, Karla Rubio, Stephanie Dobersch, Stefan Günther, Sylvia Jeratsch, Aditi Mehta, Marcus Krüger, Johannes Graumann, Werner Seeger, Gergana Dobreva, Thomas Braun, Guillermo Barreto
The majority of the eukaryotic genome is transcribed into noncoding RNAs (ncRNAs), which are important regulators of different nuclear processes by controlling chromatin structure. However, the full extent of ncRNA function has remained elusive. Here we deciphered the function of the microRNA Mirlet7d as a key regulator of bidirectionally transcribed genes. We found that nuclear Mirlet7d binds ncRNAs expressed from these genes. Mirlet7d-ncRNA duplexes are further bound by C1D, which in turn targets the RNA exosome complex and the polycomb repressive complex 2 (PRC2) to the bidirectionally active loci...
June 4, 2018: Nature Genetics
Ewa Forma, Paweł Jóźwiak, Piotr Ciesielski, Agnieszka Zaczek, Katarzyna Starska, Magdalena Bryś, Anna Krześlak
Enhancer of zest homolog 2 (EZH2) is a histone methyltransferase which plays a crucial role in cancer progression by regulation of genes involved in cellular processes such as proliferation, invasion and self-renewal. Activity and biological function of EZH2 are regulated by posttranslational modifications. It is suggested that EZH2 stability may be regulated by O-GlcNAc transferase (OGT), which is an enzyme catalyzing the addition of GlcNAc moieties to target proteins. In this study, we determined the impact of OGT on expression of EZH2 target genes FOXA1 and FOXC1, that are involved in breast cancer progression...
2018: PloS One
Lei Yang, Dawei Ge, Xi Chen, Junjun Qiu, Zhaowei Yin, Shengnai Zheng, Chunzhi Jiang
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. LncRNA has been confirmed to participate in a variety of cancers. The purpose of this study was to explore the effect of FOXP4-AS1 on the development of osteosarcoma (OS) and its underlying mechanism. FOXP4-AS1 expressions in 60 OS tissues and paracancerous tissues were detected by qRT-PCR (quantitative real-time polymerase chain reaction). We confirmed that FOXP4-AS1 was overexpressed in OS tissues than that of paracancerous tissues...
May 30, 2018: Biochemical and Biophysical Research Communications
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