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epigenetic silence

Po-Chen Chu, Peng-Chan Lin, Hsing-Yu Wu, Kuen-Tyng Lin, Christina Wu, Tanios Bekaii-Saab, Yih-Jyh Lin, Chung-Ta Lee, Jeng-Chang Lee, Ching-Shih Chen
Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation...
March 21, 2018: Oncogene
Xiang Li, Erchang Shang, Qiang Dong, Yingfeng Li, Jing Zhang, Shaohua Xu, Zuodong Zhao, Wei Shao, Cong Lv, Yong Zheng, Hailin Wang, Xiaoguang Lei, Bing Zhu, Zhuqiang Zhang
Regulation of gene expression by epigenetic modifications such as DNA methylation is crucial for developmental and disease processes, including cell differentiation and cancer development. Genes repressed by DNA methylation can be derepressed by various compounds that target DNA methyltransferases, histone deacetylases, and other regulatory factors. However, some additional, unknown mechanisms that promote DNA methylation-mediated gene silencing may exist. Chemical agents that can counteract the effects of epigenetic repression that is not regulated by DNA methyltransferases or histone deacetylases therefore may be of research interest...
March 20, 2018: Journal of Biological Chemistry
Magdalena Dryglewska, Bogdan Kolarz, Maria Majdan
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that results in uncontrolled immune system activation and overproduction of autoantibodies. The pathogenesis of the disease is complex and not fully understood, nevertheless, genetic and environmental factors play an important role. So far, about 30 genes have been identified to be involved in the SLE pathomechanism. However, not all genetically predisposed individuals develop the disease. This phenomenon can be associated with epigenetic changes that occur under the influence of environmental factors...
2018: Wiadomości Lekarskie: Organ Polskiego Towarzystwa Lekarskiego
Jiehua Zhou, Daniel Lazar, Haitang Li, Xin Xia, Sangeetha Satheesan, Paige Charlins, Denis O'Mealy, Ramesh Akkina, Sheena Saayman, Marc S Weinberg, John J Rossi, Kevin V Morris
Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential to maintain sustained viral inhibition with reduced treatment interventions. Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy. Methods: We previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), whereby small noncoding RNAs directly inhibit the transcriptional activity of HIV-1 by targeting sites within the viral promoter, specifically the 5' long terminal repeat (LTR)...
2018: Theranostics
Tao Wang, Zhong-Yi Qin, Liang-Zhi Wen, Yan Guo, Qin Liu, Zeng-Jie Lei, Wei Pan, Kai-Jun Liu, Xing-Wei Wang, Shu-Jie Lai, Wen-Jing Sun, Yan-Ling Wei, Lei Liu, Ling Guo, Yu-Qin Chen, Jun Wang, Hua-Liang Xiao, Xiu-Wu Bian, Dong-Feng Chen, Bin Wang
The evolutionarily conserved Hippo signaling pathway is a key regulator of stem cell self-renewal, differentiation, and organ size. While alterations in Hippo signaling are causally linked to uncontrolled cell growth and a broad range of malignancies, genetic mutations in the Hippo pathway are uncommon and it is unclear how the tumor suppressor function of the Hippo pathway is disrupted in human cancers. Here, we report a novel epigenetic mechanism of Hippo inactivation in the context of hepatocellular carcinoma (HCC)...
March 19, 2018: Cell Death and Differentiation
Hiroki Hamamoto, Kentaro Maemura, Kentaro Matsuo, Kohei Taniguchi, Yoshihisa Tanaka, Sugiko Futaki, Atsushi Takeshita, Akira Asai, Michihiro Hayashi, Yoshinobu Hirose, Yoichi Kondo, Kazuhisa Uchiyama
Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. We previously showed that expression of Delta-like 3 (DLL3), a member of the family of Delta/Serrate/Lag2 ligands for the Notch receptor, is silenced by aberrant DNA methylation and that overexpression of DLL3 in an HCC cell line induces cellular apoptosis. However, how DLL3 expression is regulated during hepatocarcinogenesis is still unclear. Here, we show that silencing of DLL3 during hepatocarcinogenesis is closely related to viral infection, especially hepatitis B virus (HBV) infection (p = 0...
March 19, 2018: Scientific Reports
Dai Hatakeyama, Masaki Shoji, Seiya Yamayoshi, Rina Yoh, Naho Ohmi, Shiori Takenaka, Ayaka Saitoh, Yumie Arakaki, Aki Masuda, Tsugunori Komatsu, Rina Nagano, Masahiro Nakano, Takeshi Noda, Yoshihiro Kawaoka, Takashi Kuzuhara
Histone acetylation plays crucial roles in transcriptional regulation and chromatin organization. Viral RNA of the influenza virus interacts with its nucleoprotein (NP), whose function corresponds to that of eukaryotic histones. NP regulates viral replication and has been shown to undergo acetylation by the CREB-binding protein (CBP) from the host. However, whether NP is the target of other host acetyltransferases is unknown. Here, we show that influenza virus NP undergoes acetylation by the two host acetyltransferases GCN5 and P300/CBP-associated factor (PCAF) and that this modification affects viral polymerase activities...
March 19, 2018: Journal of Biological Chemistry
Guideng Li, Alex Yick-Lun So, Reeshelle Sookram, Stephanie Wong, Jessica K Wang, Yong Ouyang, Peng He, Yapeng Su, Rafael Casellas, David Baltimore
Deregulation of several microRNAs can influence critical developmental checkpoints during hematopoiesis as well as cell functions, eventually leading to the development of autoimmune disease or cancer. We found that miR-125b is expressed in bone marrow multipotent progenitors and myeloid cells but is shut down in the B cell lineage, and the gene encoding miR-125b lacked transcriptional activation markers in B cells. To understand the biological importance of the physiological silencing of miR-125b expression in B cells, we drove its expression in the B cell lineage and found that dysregulated miR-125b expression impaired egress of immature B cells from the bone marrow to peripheral blood...
March 19, 2018: Blood
Alice Pasini, Oliver J Brand, Gisli Jenkins, Alan J Knox, Linhua Pang
Cyclooxygenase-2 (COX-2), with its main antifibrotic metabolite PGE2 , is regarded as an antifibrotic gene. Repressed COX-2 expression and deficient PGE2 have been shown to contribute to the activation of lung fibroblasts and excessive deposition of collagen in pulmonary fibrosis. We have previously demonstrated that COX-2 expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) is epigenetically silenced and can be restored by epigenetic inhibitors. This study aimed to investigate whether COX-2 downregulation induced by the profibrotic cytokine transforming growth factor-β1 (TGF-β1) in normal lung fibroblasts could be prevented by epigenetic inhibitors...
March 16, 2018: Biochimica et Biophysica Acta
Puneet, Hasan Raza Kazmi, Soni Kumari, Satendra Tiwari, A Khanna, Gopeshwar Narayan
Gastric cancer is one of the most common malignancy worldwide. The various genetic and epigenetic events have been found to be associated with its carcinogenesis. The epigenetic is a heritable and transient/reversible change in the gene expression that is not accompanied by modification in the DNA sequence. This event is characterized by the alteration in the promoter CpG island of the gene or histone modification. These events are associated with silencing of critical tumor suppressor gene and activation of oncogenes leading to carcinogenesis...
March 19, 2018: Pathology Oncology Research: POR
Ya-Wen Cheng, Chia-Jung Chou, Pei-Ming Yang
DNA 5-methylcytosine (5-mC) methylation, a key epigenetic mark, is critical for biological and pathological processes. Aberrant DNA methylation occurs in all tumor types and correlates with tumor suppressor gene silencing. DNA methylation is thought to be very stable, and active DNA demethylation remains a long-standing enigma. Recently, the ten-eleven translocation (TET) family of oxygenases are found to oxidize 5-mC to 5-hydroxymethylcytosine (5-hmC), which is prerequisite for active DNA demethylation. Both TET1 expression and global 5-hmC content are significantly reduced in colorectal cancer (CRC), the top leading cause of cancer-related death in the world...
March 2018: Surgical Oncology
Yuan Chen, Kai Leonie Schnitzler, Yunxia Ma, Miljana Nenkov, Bernhard Theis, Iver Petersen
Exploitation of autophagy might potentially improve therapeutic strategy. Here, we analyzed the protein expression of autophagy-associated genes including LC3A, LC3B, Beclin-1, p62, and Atg5 in 88-131 primary lung tumors by immunohistochemistry (IHC) on tissue-microarrays (TMAs). Additionally, the DNA methylation pattern of LC3A was investigated by bisulfite sequencing (BS) and methylation-specific-PCR (MSP). It turned out that the higher expression of LC3A protein was associated with adenocarcinoma compared to squamous cell carcinoma of lung ( p = 0...
2018: Disease Markers
Xiaohui Chen, Yujie Deng, Yi Shi, Weifeng Zhu, Yibin Cai, Chunwei Xu, Kunshou Zhu, Xiongwei Zheng, Gang Chen, Qi Xie, Guoxing Weng
Functional inactivation of human runt-related transcription factor 3 (RUNX3) through mutation or epigenetic silencing has been well-documented in many cancerous entities. In addition to gene mutation and promoter hypermethylation, cytoplasmic mislocalization has emerged as another major manifestation of RUNX3 dysfunction in malignancies including breast, colorectal and gastric cancers. The aim of the present study was to investigate whether patients with non-small cell lung cancer (NSCLC) and different RUNX3 expression patterns would have different overall survival (OS), and the associations between different patterns of clinicopathological parameters and clinical outcome...
April 2018: Oncology Letters
Yasunori Sasakura
Transgenesis is an indispensable method for elucidating the cellular and molecular mechanisms underlying biological phenomena. In Ciona, transgenic lines that have a transgene insertion in their genomes have been created. The transgenic lines are valuable because they express reporter genes in a nonmosaic manner. This nonmosaic manner allows us to accurately observe tissues and organs. The insertions of transgenes can destroy genes to create mutants. The insertional mutagenesis is a splendid method for investigating functions of genes...
2018: Advances in Experimental Medicine and Biology
Gigliola Zanghì, Shruthi S Vembar, Sebastian Baumgarten, Shuai Ding, Julien Guizetti, Jessica M Bryant, Denise Mattei, Anja T R Jensen, Laurent Rénia, Yun Shan Goh, Robert Sauerwein, Cornelus C Hermsen, Jean-François Franetich, Mallaury Bordessoulles, Olivier Silvie, Valérie Soulard, Olivier Scatton, Patty Chen, Salah Mecheri, Dominique Mazier, Artur Scherf
Heterochromatin plays a central role in the process of immune evasion, pathogenesis, and transmission of the malaria parasite Plasmodium falciparum during blood stage infection. Here, we use ChIP sequencing to demonstrate that sporozoites from mosquito salivary glands expand heterochromatin at subtelomeric regions to silence blood-stage-specific genes. Our data also revealed that heterochromatin enrichment is predictive of the transcription status of clonally variant genes members that mediate cytoadhesion in blood stage parasites...
March 13, 2018: Cell Reports
Tafadzwa Mlambo, Sandra Nitsch, Markus Hildenbeutel, Marianna Romito, Maximilian Müller, Claudia Bossen, Sven Diederichs, Tatjana I Cornu, Toni Cathomen, Claudio Mussolino
Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression...
March 10, 2018: Nucleic Acids Research
Guohong Wen, Huadong Wang, Zhaohui Zhong
BACKGROUND: Oral tumor is a heterogeneous group of tumors, in which it has several different histopathological and molecular features. Recently, genetic and epigenetic alterations are often detected in the development of oral cancer. Gene promoter hypermethylation leads to the silencing of cancer related genes without changes of genes sequence. To clarify the effect of RAS association domain family protein 1a (RASSF1A), retinoic acid receptor beta (RARβ), and E-cadherin (CDH1) promoter hypermethylation on the risk of oral cancer, we performed this meta-analysis...
March 2018: Medicine (Baltimore)
Mehrdad Zeinalian, Morteza Hashemzadeh-Chaleshtori, Rasoul Salehi, Mohammad Hassan Emami
Microsatellite instability (MSI) is a molecular hallmark for some colorectal cancers (CRCs) in which short tandem repeats are prone to mutations along with DNA sequences. It is due to DNA-mismatch-repair system deficiency because of a germline/somatic mutation in mismatch-repair (MMR) genes. The germline mutations lead to Lynch syndrome (LS) while epigenetic gene silencing results in sporadic CRC tumors. We discuss in our paper the most important clinical aspects of MSI testing in CRCs. We reviewed the most reliable relevant studies and clinical trials according to their high-quality methods, particularly within two recent decades...
2018: Advanced Biomedical Research
Kyuha Choi, Xiaohui Zhao, Andrew J Tock, Christophe Lambing, Charles J Underwood, Thomas J Hardcastle, Heïdi Serra, Juhyun Kim, Hyun Seob Cho, Jaeil Kim, Piotr A Ziolkowski, Nataliya E Yelina, Ildoo Hwang, Robert A Martienssen, Ian R Henderson
Meiotic recombination initiates from DNA double-strand breaks (DSBs) generated by SPO11 topoisomerase-like complexes. Meiotic DSB frequency varies extensively along eukaryotic chromosomes, with hotspots controlled by chromatin and DNA sequence. To map meiotic DSBs throughout a plant genome, we purified and sequenced Arabidopsis thaliana SPO11-1-oligonucleotides. SPO11-1-oligos are elevated in gene promoters, terminators, and introns, which is driven by AT-sequence richness that excludes nucleosomes and allows SPO11-1 access...
March 12, 2018: Genome Research
Charles J Underwood, Kyuha Choi, Christophe Lambing, Xiaohui Zhao, Heïdi Serra, Filipe Borges, Joe Simorowski, Evan Ernst, Yannick Jacob, Ian R Henderson, Robert A Martienssen
Eukaryotic centromeres contain the kinetochore, which connects chromosomes to the spindle allowing segregation. During meiosis, centromeres are suppressed for inter-homolog crossover, as recombination in these regions can cause chromosome missegregation and aneuploidy. Plant centromeres are surrounded by transposon-dense pericentromeric heterochromatin that is epigenetically silenced by histone 3 lysine 9 dimethylation (H3K9me2), and DNA methylation in CG and non-CG sequence contexts. However, the role of these chromatin modifications in control of meiotic recombination in the pericentromeres is not fully understood...
March 12, 2018: Genome Research
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