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Holly A F Stessman, Bo Xiong, Bradley P Coe, Tianyun Wang, Kendra Hoekzema, Michaela Fenckova, Malin Kvarnung, Jennifer Gerdts, Sandy Trinh, Nele Cosemans, Laura Vives, Janice Lin, Tychele N Turner, Gijs Santen, Claudia Ruivenkamp, Marjolein Kriek, Arie van Haeringen, Emmelien Aten, Kathryn Friend, Jan Liebelt, Christopher Barnett, Eric Haan, Marie Shaw, Jozef Gecz, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand, Charles Schwartz, R Frank Kooy, Geert Vandeweyer, Celine Helsmoortel, Corrado Romano, Antonino Alberti, Mirella Vinci, Emanuela Avola, Stefania Giusto, Eric Courchesne, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, David G Amaral, Ingrid E Scheffer, Martin B Delatycki, Paul J Lockhart, Fereydoun Hormozdiari, Benjamin Harich, Anna Castells-Nobau, Kun Xia, Hilde Peeters, Magnus Nordenskjöld, Annette Schenck, Raphael A Bernier, Evan E Eichler
Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100)...
February 13, 2017: Nature Genetics
Yin Bei, Hui Tianqian, Yu Fanyuan, Luo Haiyun, Liao Xueyang, Yang Jing, Wang Chenglin, Ye Ling
INTRODUCTION: Pulpitis is an inflammation of dental pulp produced by a response to external stimuli. The response entails substantial cellular and molecular activities. Both genetic and epigenetic regulators contribute to the occurrence of pulpitis. However, the epigenetic mechanisms are still poorly understood. In this research, we studied the role of the absent, small, or homeotic-like (ASH1L) gene in the process of pulpitis. METHODS: Human dental pulp cells (HDPCs) were stimulated with proinflammatory cytokine tumor necrosis factor alpha (TNF-α)...
December 29, 2016: Journal of Endodontics
Tianyun Wang, Hui Guo, Bo Xiong, Holly A F Stessman, Huidan Wu, Bradley P Coe, Tychele N Turner, Yanling Liu, Wenjing Zhao, Kendra Hoekzema, Laura Vives, Lu Xia, Meina Tang, Jianjun Ou, Biyuan Chen, Yidong Shen, Guanglei Xun, Min Long, Janice Lin, Zev N Kronenberg, Yu Peng, Ting Bai, Honghui Li, Xiaoyan Ke, Zhengmao Hu, Jingping Zhao, Xiaobing Zou, Kun Xia, Evan E Eichler
Recurrent de novo (DN) and likely gene-disruptive (LGD) mutations contribute significantly to autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, we sequence 189 risk genes in 1,543 Chinese ASD probands (1,045 from trios). We report an 11-fold increase in the odds of DN LGD mutations compared with expectation under an exome-wide neutral model of mutation. In aggregate, ∼4% of ASD patients carry a DN mutation in one of just 29 autism risk genes. The most prevalent gene for recurrent DN mutations is SCN2A (1...
November 8, 2016: Nature Communications
Amandine Breton, Andria Theodorou, Suleyman Aktuna, Laura Sonzogni, David Darling, Lucas Chan, Stephan Menzel, Peter J van der Spek, Sigrid M A Swagemakers, Frank Grosveld, Sjaak Philipsen, Swee Lay Thein
In 1993, we described an English family with beta-thalassaemia that was not linked to the beta-globin locus. Whole genome sequence analyses revealed potential causative mutations in 15 different genes, of which 4 were consistently and uniquely associated with the phenotype in all 7 affected family members, also confirmed by genetic linkage analysis. Of the 4 genes, which are present in a centromeric region of chromosome 1, ASH1L was proposed as causative through functional mRNA knock-down and chromatin-immunoprecipitation studies in human erythroid progenitor cells...
July 19, 2016: British Journal of Haematology
Sebastian T Balbach, Stuart H Orkin
Histone H3 lysine 36 dimethylation (H3K36me2), a modification associated with transcriptional activation, is required for mixed-lineage leukemia-dependent transcription and leukemic transformation. In this issue of Cancer Discovery, Zhu and colleagues map the network of readers, writers, and erasers of H3K36me2 and uncover the ASH1L histone methyltransferase as a novel target for therapeutic intervention. Cancer Discov; 6(7); 700-2. ©2016 AACR.See related article by Zhu and colleagues, p. 770.
July 2016: Cancer Discovery
Τao Zhu, Chen Liang, Dongdong Li, Miaomiao Tian, Sanxiong Liu, Guanjun Gao, Ji-Song Guan
Activity-dependent transcription is critical for the regulation of long-term synaptic plasticity and plastic rewiring in the brain. Here, we report that the transcription of neurexin1α (nrxn1α), a presynaptic adhesion molecule for synaptic formation, is regulated by transient neuronal activation. We showed that 10 minutes of firing at 50 Hz in neurons repressed the expression of nrxn1α for 24 hours in a primary cortical neuron culture through a transcriptional repression mechanism. By performing a screening assay using a synthetic zinc finger protein (ZFP) to pull down the proteins enriched near the nrxn1α promoter region in vivo, we identified that Ash1L, a histone methyltransferase, is enriched in the nrxn1α promoter...
2016: Scientific Reports
Li Zhu, Qin Li, Stephen H K Wong, Min Huang, Brianna J Klein, Jinfeng Shen, Larissa Ikenouye, Masayuki Onishi, Dominik Schneidawind, Corina Buechele, Loren Hansen, Jesús Duque-Afonso, Fangfang Zhu, Gloria Mas Martin, Or Gozani, Ravindra Majeti, Tatiana G Kutateladze, Michael L Cleary
UNLABELLED: Numerous studies in multiple systems support that histone H3 lysine 36 dimethylation (H3K36me2) is associated with transcriptional activation; however, the underlying mechanisms are not well defined. Here, we show that the H3K36me2 chromatin mark written by the ASH1L histone methyltransferase is preferentially bound in vivo by LEDGF, a mixed-lineage leukemia (MLL)-associated protein that colocalizes with MLL, ASH1L, and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild-type MLL proteins to chromatin at key leukemia target genes and is a crucial regulator of MLL-dependent transcription and leukemic transformation...
July 2016: Cancer Discovery
Akihiro Fujimoto, Mayuko Furuta, Yasushi Totoki, Tatsuhiko Tsunoda, Mamoru Kato, Yuichi Shiraishi, Hiroko Tanaka, Hiroaki Taniguchi, Yoshiiku Kawakami, Masaki Ueno, Kunihito Gotoh, Shun-Ichi Ariizumi, Christopher P Wardell, Shinya Hayami, Toru Nakamura, Hiroshi Aikata, Koji Arihiro, Keith A Boroevich, Tetsuo Abe, Kaoru Nakano, Kazuhiro Maejima, Aya Sasaki-Oku, Ayako Ohsawa, Tetsuo Shibuya, Hiromi Nakamura, Natsuko Hama, Fumie Hosoda, Yasuhito Arai, Shoko Ohashi, Tomoko Urushidate, Genta Nagae, Shogo Yamamoto, Hiroki Ueda, Kenji Tatsuno, Hidenori Ojima, Nobuyoshi Hiraoka, Takuji Okusaka, Michiaki Kubo, Shigeru Marubashi, Terumasa Yamada, Satoshi Hirano, Masakazu Yamamoto, Hideki Ohdan, Kazuaki Shimada, Osamu Ishikawa, Hiroki Yamaue, Kazuki Chayama, Satoru Miyano, Hiroyuki Aburatani, Tatsuhiro Shibata, Hidewaki Nakagawa
Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions...
May 2016: Nature Genetics
Ibrahim E Elsemman, Adil Mardinoglu, Saeed Shoaie, Taysir H Soliman, Jens Nielsen
Hepatitis C virus (HCV) infection is a worldwide healthcare problem; however, traditional treatment methods have failed to cure all patients, and HCV has developed resistance to new drugs. Systems biology-based analyses could play an important role in the holistic analysis of the impact of HCV on hepatocellular metabolism. Here, we integrated HCV assembly reactions with a genome-scale hepatocyte metabolic model to identify metabolic targets for HCV assembly and metabolic alterations that occur between different HCV progression states (cirrhosis, dysplastic nodule, and early and advanced hepatocellular carcinoma (HCC)) and healthy liver tissue...
April 26, 2016: Molecular BioSystems
Chryssa Kanellopoulou, Timothy Gilpatrick, Gokhul Kilaru, Patrick Burr, Cuong K Nguyen, Aaron Morawski, Michael J Lenardo, Stefan A Muljo
Members of the miR-290 family are the most abundantly expressed microRNAs (miRNAs) in mouse embryonic stem cells (ESCs). They regulate aspects of differentiation, pluripotency, and proliferation of ESCs, but the molecular program that they control has not been fully delineated. In the absence of Dicer, ESCs fail to express mature miR-290 miRNAs and have selective aberrant overexpression of Hoxa, Hoxb, Hoxc, and Hoxd genes essential for body plan patterning during embryogenesis, but they do not undergo a full differentiation program...
December 8, 2015: Stem Cell Reports
Michelle L Brinkmeier, Krista A Geister, Morgan Jones, Meriam Waqas, Ivan Maillard, Sally A Camper
Chromatin remodeling influences gene expression in developing and adult organisms. Active and repressive marks of histone methylation dictate the embryonic expression boundaries of developmentally regulated genes, including the Hox gene cluster. Drosophila ash1 (absent, small or homeotic discs 1) gene encodes a histone methyltransferase essential for regulation of Hox gene expression that interacts genetically with other members of the trithorax group (TrxG). While mammalian members of the mixed lineage leukemia (Mll) family of TrxG genes have roles in regulation of Hox gene expression, little is known about the expression and function of the mammalian ortholog of the Drosophila ash1 gene, Ash1-like (Ash1l)...
November 2015: Biology of Reproduction
David S Rogawski, Juliano Ndoj, Hyo Je Cho, Ivan Maillard, Jolanta Grembecka, Tomasz Cierpicki
ASH1L (absent, small, or homeotic-like 1) is a histone methyltransferase (HMTase) involved in gene activation that is overexpressed in multiple forms of cancer. Previous studies of ASH1L's catalytic SET domain identified an autoinhibitory loop that blocks access of histone substrate to the enzyme active site. Here, we used both nuclear magnetic resonance and X-ray crystallography to identify conformational dynamics in the ASH1L autoinhibitory loop. Using site-directed mutagenesis, we found that point mutations in the autoinhibitory loop that perturb the structure of the SET domain result in decreased enzyme activity, indicating that the autoinhibitory loop is not a simple gate to the active site but is rather a key feature critical to ASH1L function...
September 8, 2015: Biochemistry
Mohammad S Eram, Ekaterina Kuznetsova, Fengling Li, Evelyne Lima-Fernandes, Steven Kennedy, Irene Chau, Cheryl H Arrowsmith, Matthieu Schapira, Masoud Vedadi
BACKGROUND: Dysregulation of methylation of lysine 36 on histone H3 (H3K36) have been implicated in a variety of diseases including cancers. ASH1L and SETD2 are two enzymes among others that catalyze H3K36 methylation. H3K4 methylation has also been reported for ASH1L. METHODS: Radioactivity-based enzyme assays, Western and immunoblotting using specific antibodies and molecular modeling were used to characterize substrate specificity of ASH1L and SETD2. RESULTS: Here we report on the assay development and kinetic characterization of ASH1L and SETD2 and their substrate specificities in vitro...
September 2015: Biochimica et Biophysica Acta
Hyuna Sung, Howard H Yang, Han Zhang, Qi Yang, Nan Hu, Ze-Zhong Tang, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Jin-Hu Fan, You-Lin Qiao, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Maxwell P Lee, Stephen J Chanock, Sanford M Dawsey, Neal D Freedman, Christian C Abnet, Alisa M Goldstein, Kai Yu, Philip R Taylor, Paula L Hyland
BACKGROUND: Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk. METHODS: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry...
August 2015: International Journal of Epidemiology
Morgan Jones, Jennifer Chase, Michelle Brinkmeier, Jing Xu, Daniel N Weinberg, Julien Schira, Ann Friedman, Sami Malek, Jolanta Grembecka, Tomasz Cierpicki, Yali Dou, Sally A Camper, Ivan Maillard
Rapidly cycling fetal and neonatal hematopoietic stem cells (HSCs) generate a pool of quiescent adult HSCs after establishing hematopoiesis in the bone marrow. We report an essential role for the trithorax group gene absent, small, or homeotic 1-like (Ash1l) at this developmental transition. Emergence and expansion of Ash1l-deficient fetal/neonatal HSCs were preserved; however, in young adult animals, HSCs were profoundly depleted. Ash1l-deficient adult HSCs had markedly decreased quiescence and reduced cyclin-dependent kinase inhibitor 1b/c (Cdkn1b/1c) expression and failed to establish long-term trilineage bone marrow hematopoiesis after transplantation to irradiated recipients...
May 2015: Journal of Clinical Investigation
Lanxin Liu, Sarah Kimball, Hui Liu, Andreana Holowatyj, Zeng-Quan Yang
Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome...
February 10, 2015: Oncotarget
Hye Rim Oh, Chang Hyeok An, Nam Jin Yoo, Sug Hyung Lee
BACKGROUND: Metabolic reprogramming is an emerging topic in cancer research. However, genetic alterations in genes encoding enzymes involved in amino acid metabolism are largely unknown. The aim of this study was to explore whether genes known to be involved in amino acid metabolism are mutated in gastric cancer (GC) and/or colorectal cancer (CRC). METHODS: Through a public database search, we found that a number of genes known to be involved in amino acid metabolism, i...
December 2014: Cellular Oncology (Dordrecht)
Marianna Colamaio, Francesca Puca, Elvira Ragozzino, Marica Gemei, Myriam Decaussin-Petrucci, Concetta Aiello, André Uchimura Bastos, Antonella Federico, Gennaro Chiappetta, Luigi Del Vecchio, Liborio Torregrossa, Sabrina Battista, Alfredo Fusco
CONTEXT: A previous micro-RNA expression profile of thyroid follicular adenomas identified miR-142 precursor among the miRNAs downregulated in the neoplastic tissues compared to normal thyroid gland. OBJECTIVE: The aim of this work has been to assess the expression of miR-142-3p in a large panel of follicular thyroid adenomas and carcinomas and evaluate its effect on thyroid cell proliferation and target expression. DESIGN: The expression of miR-142-3p was analyzed by qRT-PCR in thyroid follicular adenomas and carcinomas, compared to normal thyroids...
January 2015: Journal of Clinical Endocrinology and Metabolism
Bhavneet Bhinder, David Shum, Mu Li, Glorymar Ibáñez, Alexander V Vlassov, Susan Magdaleno, Hakim Djaballah
There is an acceptance that plasmid-based delivery of interfering RNA always generates the intended targeting sequences in cells, making it as specific as its synthetic counterpart. However, recent studies have reported on cellular inefficiencies of the former, especially in light of emerging gene discordance at inter-screen level and across formats. Focusing primarily on the TRC plasmid-based shRNA hairpins, we reasoned that alleged specificities were perhaps compromised due to altered processing; resulting in a multitude of random interfering sequences...
2014: PloS One
Dmitri Mouradov, Clare Sloggett, Robert N Jorissen, Christopher G Love, Shan Li, Antony W Burgess, Diego Arango, Robert L Strausberg, Daniel Buchanan, Samuel Wormald, Liam O'Connor, Jennifer L Wilding, David Bicknell, Ian P M Tomlinson, Walter F Bodmer, John M Mariadason, Oliver M Sieber
Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas...
June 15, 2014: Cancer Research
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