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Epigenetic silencing

Jiajin Yang, Heng Ge, Caroline J Poulton, Susan L Hogan, Yichun Hu, Britta E Jones, Candace D Henderson, Elizabeth A McInnis, William F Pendergraft, J Charles Jennette, Ronald J Falk, Dominic J Ciavatta
BACKGROUND: Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease characterized by destructive vascular inflammation. Two prominent ANCA autoantigens are myeloperoxidase (MPO) and proteinase 3 (PR3), and transcription of MPO and PRTN3, the genes encoding the autoantigens, is associated with disease activity. We investigated whether patients with AAV have alterations in histone modifications, particularly those associated with transcriptional activation, at MPO and PRTN3...
2016: Clinical Epigenetics
Dinesh Singh Tekcham, Satish S Poojary, Shushruta Bhunia, Mustafa Ahmed Barbhuiya, Sanjeev Gupta, Braj Raj Shrivastav, Pramod Kumar Tiwari
BACKGROUND & OBJECTIVES: Loss of function of adenomatous polyposis coli (APC) has been reported in cancer. The two promoters of APC, 1A and 1B also have roles in cancer. But, the epigenetic role of APC promoters is not yet clear in gallbladder cancer (GBC) and gallstone diseases (GSD). We undertook this study to determine the epigenetic role of APC in GBC and GSD. METHODS: Methylation-specific (MS)-PCR was used to analyze the methylation of APC gene. The expression of APC gene was studied by semi-quantitative PCR, real-time PCR and immunohistochemistry (IHC) in GBC, GSD and adjacent normal tissues...
May 2016: Indian Journal of Medical Research
David Agustriawan, Chien-Hung Huang, Jim Jinn-Chyuan Sheu, Shan-Chih Lee, Jeffrey J P Tsai, Nilubon Kurubanjerdjit, Ka-Lok Ng
Epigenetic regulation has been linked to the initiation and progression of cancer. Aberrant expression of microRNAs (miRNAs) is one such mechanism that can activate or silence oncogenes (OCGs) and tumor suppressor genes (TSGs) in cells. A growing number of studies suggest that miRNA expression can be regulated by methylation modification, thus triggering cancer development. However, there is no comprehensive in silico study concerning miRNA regulation by direct DNA methylation in cancer. Ovarian serous cystadenocarcinoma (OSC) was therefore chosen as a tumor model for the present work...
October 1, 2016: Computational Biology and Chemistry
E Balada, L Felip, J Ordi-Ros, M Vilardell-Tarrés
We evaluated the transcriptional expression of DUSP23 in CD4+ T cells from 30 SLE patients and 30 healthy controls. DUSP23 mRNA levels were considerably higher in the patients group: 1,490 ± 1,713 versus 294,1 ± 204,2. None association was found between DUSP23 mRNA expression and the presence of typical serological and clinical parameters associated to SLE. Meaningful statistical values were obtained in the patients group between the levels of DUSP23 and ITGAL, PRF1, and CD40L. Similarly, transcript levels of different DNA methylation-related enzymes (DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4) were also positively correlated to the expression of DUSP23...
October 13, 2016: Clinical and Experimental Immunology
Takamasa Hirano, Hidetoshi Hasuwa, Haruhiko Siomi
The mouse testis has served as a popular model system to study a wide range of biological processes, including germ cell development, meiosis, epigenetic changes of chromatin, transposon silencing, and small RNA-mediated epigenetic modifications. PIWI-interacting RNAs (piRNAs) are a class of small RNAs that are almost exclusively expressed in animal gonads. They repress transposons by forming effector complexes with PIWI proteins to maintain genome integrity of the germline. Here we describe detailed procedures of how to produce monoclonal antibodies against a mouse nuclear PIWI protein, MIWI2, which functions in de novo DNA methylation of target transposon loci...
2017: Methods in Molecular Biology
Jing Du, Martin Neuenschwander, Yong Yu, J Henry M Däbritz, Nina-Rosa Neuendorff, Kolja Schleich, Aitomi Bittner, Maja Milanovic, Gregor Beuster, Silke Radetzki, Edgar Specker, Maurice Reimann, Frank Rosenbauer, Stephan Mathas, Philipp Lohneis, Michael Hummel, Bernd Dörken, Jens Peter von Kries, Soyoung Lee, Clemens A Schmitt
Classical Hodgkin's lymphoma (cHL), although originating from B-cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling...
October 12, 2016: Blood
Helen Ross-Adams, Stephen Ball, Kate Lawrenson, Silvia Halim, Roslin Russell, Claire Wells, Siri H Strand, Torben F Ørntoft, Melissa Larson, Sebastian Armasu, Charles E Massie, Mohammad Asim, Martin M Mortensen, Michael Borre, Kathryn Woodfine, Anne Y Warren, Alastair D Lamb, Jonathan Kay, Hayley Whitaker, Antonio Ramos-Montoya, Adele Murrell, Karina D Sørensen, Brooke L Fridley, Ellen L Goode, Simon A Gayther, John Masters, David E Neal, Ian G Mills
Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues...
October 9, 2016: Oncotarget
Moon Kyung Joo, Jong-Jae Park, Hoon Jai Chun
Homeobox genes, including HOX and non-HOX genes, have been identified to be expressed aberrantly in solid tumors. In gastrointestinal (GI) cancers, most studies have focused on the function of non-HOX genes including caudal-related homeobox transcription factor 1 (CDX1) and CDX2. CDX2 is a crucial factor in the development of pre-cancerous lesions such as Barrett's esophagus or intestinal metaplasia in the stomach, and its tumor suppressive role has been investigated in colorectal cancers. Recently, several HOX genes were reported to have specific roles in GI cancers; for example, HOXA13 in esophageal squamous cell cancer and HOXB7 in stomach and colorectal cancers...
October 7, 2016: World Journal of Gastroenterology: WJG
Tomoko Kawai, Kenichiro Hata
Foetal environmental factors, including maternal nutrition, hormonal disturbance, and chemical exposure, affect foetal growth and can cause birth defects. Recent studies have shown the link of poor foetal growth with increased risks of coronary heart disease, type II diabetes, kidney disease, and brain disorders in adulthood. Epigenetic modifications, such as DNA methylation and histone modifications, are involved in tissue- and developmental stage-specific gene expression and silencing, and they can be transmitted stably through mitotic cell division, thereby inducing long-term changes in gene regulation...
2016: Nihon Eiseigaku Zasshi. Japanese Journal of Hygiene
Shota Suzuki, Yota Murakami, Shinya Takahata
Epigenetic marks determine cell fate via numerous reader proteins. H3K36 methylation is a common epigenetic mark that is thought to be associated with the activities of the RNA polymerase 2 C-terminal domain. We discuss a novel silencing mechanism regulated by Set2-dependent H3K36 methylation that involves exosome-dependent RNA processing.
October 10, 2016: Transcription
Shunhua Zhang, Linyuan Shen, Yudong Xia, Qiong Yang, Xuewei Li, Guoqing Tang, Yanzhi Jiang, Jinyong Wang, Mingzhou Li, Li Zhu
Obese and lean type pig breeds exhibit differences in their fat deposits and fatty acid composition. Here, we compared the effect of genome-wide DNA methylation on fatty acid metabolism between Landrace pigs (LP, leaner) and Rongchang pigs (RP, fatty). We found that LP backfat (LBF) had a higher polyunsaturated fatty acid content but a lower adipocyte volume than RP backfat (RBF). LBF exhibited higher global DNA methylation levels at the genome level than RBF. A total of 483 differentially methylated regions (DMRs) were located in promoter regions, mainly affecting olfactory and sensory activity and lipid metabolism...
October 10, 2016: Scientific Reports
Sheng Zeng, Yuyu Yang, Xian Cheng, Bisheng Zhou, Ping Li, Yuhao Zhao, Xiaocen Kong, Yong Xu
Differentiation of B lymphocytes into isotope-specific plasma cells represents a hallmark event in adaptive immunity. During B cell maturation, expression of the class II transactivator (CIITA) gene is down-regulated although the underlying epigenetic mechanism is not completely defined. Here we report that hypermethylated in cancer 1 (HIC1) was up-regulated in differentiating B lymphocytes paralleling CIITA repression. Over-expression of HIC1 directly repressed endogenous CIITA transcription in B cells. Reporter assay and chromatin immunoprecipitation (ChIP) assay confirmed that HIC1 bound to the proximal CIITA type III promoter (-545/-113); mutation of a conserved HIC1 site within this region abrogated CIITA trans-repression...
October 6, 2016: Biochimica et Biophysica Acta
Valentina Damiano, Giulia Brisotto, Silvia Borgna, Alessandra di Gennaro, Michela Armellin, Tiziana Perin, Michela Guardascione, Roberta Maestro, Manuela Santarosa
Loss of expression of miR-200 family members has been implicated in cellular plasticity, a phenomenon that accounts for epithelial-to-mesenchymal transition (EMT) and stem-like features of many carcinomas and is considered a major cause of tumor aggressiveness and drug resistance. Nevertheless, the mechanisms of miR-200 downregulation in breast cancer are still largely unknown. Here we show that miR-200c expression inversely correlates with miR-200c/miR-141 locus methylation in triple-negative breast tumors (TNBC)...
September 22, 2016: Genes, Chromosomes & Cancer
Federica Federici, Aristea Magaraki, Evelyne Wassenaar, Catherina J H van Veen-Buurman, Christine van de Werken, Esther B Baart, Joop S E Laven, J Anton Grootegoed, Joost Gribnau, Willy M Baarends
In mouse female preimplantation embryos, the paternal X chromosome (Xp) is silenced by imprinted X chromosome inactivation (iXCI). This requires production of the noncoding Xist RNA in cis, from the Xp. The Xist locus on the maternally inherited X chromosome (Xm) is refractory to activation due to the presence of an imprint. Paternal inheritance of an Xist deletion (XpΔXist) is embryonic lethal to female embryos, due to iXCI abolishment. Here, we circumvented the histone-to-protamine and protamine-to-histone transitions of the paternal genome, by fertilization of oocytes via injection of round spermatids (ROSI)...
October 2016: PLoS Genetics
Thomas D Brekke, Lindy A Henry, Jeffrey M Good
The importance of regulatory incompatibilities to the early stages of speciation remains unclear. Hybrid mammals often show extreme parent-of-origin growth effects that are thought to be a consequence of disrupted genetic imprinting (parent-specific epigenetic gene silencing) during early development. Here we test the long-standing hypothesis that abnormal hybrid growth reflects disrupted gene expression due to loss of imprinting (LOI) in hybrid placentas, resulting in dosage imbalances between paternal growth factors and maternal growth repressors...
October 7, 2016: Evolution; International Journal of Organic Evolution
Yifan Zhou, Daman Kumari, Nicholas Sciascia, Karen Usdin
BACKGROUND: Fragile X syndrome (FXS), a common cause of intellectual disability and autism, results from the expansion of a CGG-repeat tract in the 5' untranslated region of the FMR1 gene to >200 repeats. Such expanded alleles, known as full mutation (FM) alleles, are epigenetically silenced in differentiated cells thus resulting in the loss of FMRP, a protein important for learning and memory. The timing of repeat expansion and FMR1 gene silencing is controversial. METHODS: We monitored the repeat size and methylation status of FMR1 alleles with expanded CGG repeats in patient-derived induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) that were grown for extended period of time either as stem cells or differentiated into neurons...
2016: Molecular Autism
Stefanie Rosa, Susan Duncan, Caroline Dean
Antisense transcription through genic regions is pervasive in most genomes; however, its functional significance is still unclear. We are studying the role of antisense transcripts (COOLAIR) in the cold-induced, epigenetic silencing of Arabidopsis FLOWERING LOCUS C (FLC), a regulator of the transition to reproduction. Here we use single-molecule RNA FISH to address the mechanistic relationship of FLC and COOLAIR transcription at the cellular level. We demonstrate that while sense and antisense transcripts can co-occur in the same cell they are mutually exclusive at individual loci...
October 7, 2016: Nature Communications
Tingxiu Xiang, Yichao Fan, Chunhong Li, Lili Li, Ying Ying, Junhao Mu, Weiyan Peng, Yixiao Feng, Michael Oberst, Kathleen Kelly, Guosheng Ren, Qian Tao
Wnt signaling plays an important role in breast carcinogenesis. DAPPER2 (DACT2) functions as an inhibitor of canonical Wnt signaling and plays distinct roles in different cell contexts, with its role in breast tumorigenesis unclear. We investigated DACT2 expression in breast cancer cell lines and primary tumors, as well as its functions and molecular mechanisms. Results showed that DACT2 expression was silenced in 9/9 of cell lines. Promoter CpG methylation of DACT2 was detected in 89% (8/9) of cell lines, as well as in 73% (107/147) of primary tumors, but only in 20% (1/5) of surgical margin tissues and in none of normal breast tissues...
September 29, 2016: Oncotarget
Cristina Morales Torres, Alva Biran, Matthew J Burney, Harshil Patel, Tristan Henser-Brownhill, Ayelet-Hashahar Shapira Cohen, Yilong Li, Rotem Ben-Hamo, Emma Nye, Bradley Spencer-Dene, Probir Chakravarty, Sol Efroni, Nik Matthews, Tom Misteli, Eran Meshorer, Paola Scaffidi
Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which cells within a tumor can sustain the long-term cancer growth. Numerous cancer types exhibit high inter- and intratumor heterogeneity of H1.0, with H1.0 levels correlating with tumor differentiation status, patient survival, and, at the single-cell level, cancer stem cell markers. Silencing of H1.0 promotes maintenance of self-renewing cells by inducing derepression of megabase-sized gene domains harboring downstream effectors of oncogenic pathways...
September 30, 2016: Science
Simon Hauri, Federico Comoglio, Makiko Seimiya, Moritz Gerstung, Timo Glatter, Klaus Hansen, Ruedi Aebersold, Renato Paro, Matthias Gstaiger, Christian Beisel
Polycomb group (PcG) proteins are major determinants of gene silencing and epigenetic memory in higher eukaryotes. Here, we systematically mapped the human PcG complexome using a robust affinity purification mass spectrometry approach. Our high-density protein interaction network uncovered a diverse range of PcG complexes. Moreover, our analysis identified PcG interactors linking them to the PcG system, thus providing insight into the molecular function of PcG complexes and mechanisms of recruitment to target genes...
October 4, 2016: Cell Reports
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