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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
István Bock, Krisztina Németh, Klára Pentelényi, Péter Balicza, Anna Balázs, Mária Judit Molnár, Viktor Román, József Nagy, György Lévay, Julianna Kobolák, András Dinnyés
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with unknown genetic and environmental causation in most of the affected individuals. On the other hand, there are a growing number of ASD-associated syndromes, where the exact genetic origin can be revealed. Here we report a method, which included the targeted next generation sequencing (NGS) and filtering of 101 ASD associated genes, followed by database search. Next, RNA sequencing was used to study the region of interest at the transcriptional level...
September 17, 2016: Gene
Marco Benevento, Giovanni Iacono, Martijn Selten, Wei Ba, Astrid Oudakker, Monica Frega, Jason Keller, Roberta Mancini, Elly Lewerissa, Tjitske Kleefstra, Henk G Stunnenberg, Huiqing Zhou, Hans van Bokhoven, Nael Nadif Kasri
Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra-syndrome-associated protein EHMT1 plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression...
July 20, 2016: Neuron
Euthymia Vargiami, Athina Ververi, Hamda Al-Mutawa, Georgia Gioula, Spyridon Gerou, Fotios Rouvalis, Marios Kambouris, Dimitrios I Zafeiriou
Kleefstra syndrome is characterized by hypotonia, developmental delay, dysmorphic features, congenital heart defects, and so forth. It is caused by 9q34.3 microdeletions or EHMT1 mutations. Herein a 20-month-old girl with Kleefstra syndrome, due to a de novo subterminal deletion, is described. She exhibits a rare and complex cardiopathy, encompassing multiple coronary artery microfistulas, VSD/ASD, and PFO.
2016: Case Reports in Genetics
Xu He, Oana Caluseriu, Ratika Srivastava, Anne Marie Denny, Francois V Bolduc
Kleefstra syndrome (KS; OMIM #610253), formerly known as the 9q subtelomeric deletion syndrome, is an autosomal dominant cause of intellectual disability (ID) characterized by hypotonia and facial dysmorphisms.(1,2) The cause of KS is attributed to haploinsufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene (OMIM *607001) located at chromosome 9q34.3 (i.e., distal long arm of chromosome 9), either by microdeletion or point mutation. EHMT1 encodes a histone H3 methyltransferase at position Lys-9 (H3K9)...
April 2016: Neurology. Genetics
Andrew E Fry, Elliott Rees, Rose Thompson, Kiran Mantripragada, Penny Blake, Glyn Jones, Sian Morgan, Sian Jose, Hood Mugalaasi, Hayley Archer, Emma McCann, Angus Clarke, Clare Taylor, Sally Davies, Frances Gibbon, Johann Te Water Naude, Louise Hartley, Gareth Thomas, Catharine White, Jaya Natarajan, Rhys H Thomas, Cheney Drew, Seo-Kyung Chung, Mark I Rees, Peter Holmans, Michael J Owen, George Kirov, Daniela T Pilz, Michael P Kerr
BACKGROUND: Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. METHODS: We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation...
2016: BMC Medical Genetics
Lena Ebbers, Karen Runge, Hans Gerd Nothwang
Histone methylation is an important epigenetic mark leading to changes in DNA accessibility and transcription. Here, we investigate immunoreactivity against the euchromatic histone-lysine N-methyltransferase EHMT2 and its catalyzed mono- and dimethylation marks at histone 3 lysine 9 (H3K9me1 and H3K9me2) during postnatal differentiation of the mouse central auditory system. In the brainstem, expression of EHMT2 was high in the first postnatal week and down-regulated thereafter. In contrast, immunoreactivity in the auditory cortex (AC) remained high during the first year of life...
August 2016: Cell and Tissue Research
James R Priest, Kazutoyo Osoegawa, Nebil Mohammed, Vivek Nanda, Ramendra Kundu, Kathleen Schultz, Edward J Lammer, Santhosh Girirajan, Todd Scheetz, Daryl Waggott, Francois Haddad, Sushma Reddy, Daniel Bernstein, Trudy Burns, Jeffrey D Steimle, Xinan H Yang, Ivan P Moskowitz, Matthew Hurles, Richard P Lifton, Debbie Nickerson, Michael Bamshad, Evan E Eichler, Seema Mital, Val Sheffield, Thomas Quertermous, Bruce D Gelb, Michael Portman, Euan A Ashley
Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD)...
April 2016: PLoS Genetics
Natalie Trump, Amy McTague, Helen Brittain, Apostolos Papandreou, Esther Meyer, Adeline Ngoh, Rodger Palmer, Deborah Morrogh, Christopher Boustred, Jane A Hurst, Lucy Jenkins, Manju A Kurian, Richard H Scott
BACKGROUND: We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. METHODS: In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. RESULTS: We identified causative mutations in 71/400 patients (18%)...
May 2016: Journal of Medical Genetics
Mónica D Martín-De Saro, Juan M Valdés-Miranda, Lautaro Plaza-Benhumea, Adrián Pérez-Cabrera, Luz M Gonzalez-Huerta, Roberto Guevara-Yañez, Sergio A Cuevas-Covarrubias
Rearrangements of the distal region of 9p are important chromosome imbalances in human beings. Trisomy 9p is the fourth most frequent chromosome anomaly and is a clinically recognizable syndrome. Kleefstra syndrome, previously named 9q subtelomeric deletion syndrome, is either caused by a submicroscopic deletion in 9q34.3 or an intragenic mutation of EHMT1. We report a Mexican male patient with abnormal development, dysmorphism, systemic anomalies and a complex chromosomal rearrangement (CCR). GTG-banding revealed a 46,XY,add(9)(q34...
2015: Cytogenetic and Genome Research
Susanne Schmidt, Heidi E Nag, Bente S Hunn, Gunnar Houge, Lise B Hoxmark
The present study aimed to further our understanding of Kleefstra syndrome, especially regarding motor function and behavioral characteristics. In total, four males and four females between two and 27 years of age with a genetically confirmed diagnosis of Kleefstra syndrome and their parents participated in this study. Four patients had 9q34.3 deletions that caused Euchromatin Histone Methyl Transferase 1 (EHMT1) haplo-insufficiency, and four patients harbored EHMT1 mutations. The motor function was evaluated via systematic observation...
April 2016: European Journal of Medical Genetics
Giovanna Marchese, Francesca Rizzo, Anna Guacci, Alessandro Weisz, Giangennaro Coppola
No abstract text is available yet for this article.
May 2016: Neurological Sciences
Anna Greißel, Mihaela Culmes, Rainer Burgkart, Alexander Zimmermann, Hans-Henning Eckstein, Alma Zernecke, Jaroslav Pelisek
BACKGROUND: The aim of the study was to analyze histone acetylation, methylation, and the expression of their corresponding transferases in atherosclerotic plaques of patients with carotid artery stenosis. METHODS: Atherosclerotic tissue from our biobank (n=80) was divided into various segments covering all plaque stages and classified according to the American Heart Association. The plaques were assigned to early (types I-III) or advanced (types V-VII) stage group of atherosclerosis...
March 2016: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
Jumpei Yamazaki, Rodolphe Taby, Jaroslav Jelinek, Noel J M Raynal, Matteo Cesaroni, Sherry A Pierce, Steven M Kornblau, Carlos E Bueso-Ramos, Farhad Ravandi, Hagop M Kantarjian, Jean-Pierre J Issa
BACKGROUND: Acute myeloid leukemia (AML) is curable in a subset of cases. The DNA methylation regulator TET2 is frequently mutated in AML, and we hypothesized that studying TET2-specific differentially methylated CpGs (tet2-DMCs) improves AML classification. METHODS: We used bisulfite pyrosequencing to analyze the methylation status of four tet2-DMCs (SP140, MCCC1, EHMT1, and MTSS1) in a test group of 94 consecutive patients and a validation group of 92 consecutive patients treated with cytarabine-based chemotherapy...
February 2016: Journal of the National Cancer Institute
Aline Renneville, Peter Van Galen, Matthew C Canver, Marie McConkey, John M Krill-Burger, David M Dorfman, Edward B Holson, Bradley E Bernstein, Stuart H Orkin, Daniel E Bauer, Benjamin L Ebert
Fetal hemoglobin (HbF, α2γ2) induction is a well-validated strategy for sickle cell disease (SCD) treatment. Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. EHMT1/2 catalyze mono- and dimethylation of lysine 9 on histone 3 (H3K9), raising the possibility that H3K9Me2, a repressive chromatin mark, plays a role in silencing γ-globin expression. In primary human adult erythroid cells, UNC0638 and EHMT1 or EHMT2 short hairpin RNA-mediated knockdown significantly increased γ-globin expression, HbF synthesis, and the percentage of cells expressing HbF...
October 15, 2015: Blood
Edward Curry, Ian Green, Nadine Chapman-Rothe, Elham Shamsaei, Sarah Kandil, Fanny L Cherblanc, Luke Payne, Emma Bell, Thota Ganesh, Nitipol Srimongkolpithak, Joachim Caron, Fengling Li, Anthony G Uren, James P Snyder, Masoud Vedadi, Matthew J Fuchter, Robert Brown
BACKGROUND: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks...
2015: Clinical Epigenetics
Jamie M Kramer
The euchromatin histone methyltransferases (EHMTs) are an evolutionarily conserved protein family that are known for their ability to dimethylate histone 3 at lysine 9 in euchromatic regions of the genome. In mammals there are two EHMT proteins, G9a, encoded by EHMT2, and GLP, encoded by EHMT1. EHMTs have diverse roles in the differentiation of different tissues and cell types and are involved in adult-specific processes like memory, drug addiction, and immune response. This review discusses recent findings from rodent and Drosophila models that are beginning to reveal the broad biological role and complex mechanistic functioning of EHMT proteins...
February 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Gilles Maussion, Alpha B Diallo, Carolina O Gigek, Elizabeth S Chen, Liam Crapper, Jean-Francois Théroux, Gary G Chen, Cristina Vasuta, Carl Ernst
Several neurodevelopmental disorders (NDDs) are caused by mutations in genes expressed in fetal brain, but little is known about these same genes in adult human brain. Here, we test the hypothesis that genes associated with NDDs continue to have a role in adult human brain to explore the idea that NDD symptoms may be partially a result of their adult function rather than just their neurodevelopmental function. To demonstrate adult brain function, we performed expression analyses and ChIPseq in human neural stem cell(NSC) lines at different developmental stages and adult human brain, targeting two genes associated with NDDs, SATB2 and EHMT1, and the WNT signaling gene TCF7L2, which has not been associated with NDDs...
October 2015: Human Genetics
William N Pappano, Jun Guo, Yupeng He, Debra Ferguson, Sujatha Jagadeeswaran, Donald J Osterling, Wenqing Gao, Julie K Spence, Marina Pliushchev, Ramzi F Sweis, Fritz G Buchanan, Michael R Michaelides, Alexander R Shoemaker, Chris Tse, Gary G Chiang
Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types...
2015: PloS One
C O Gigek, E S Chen, V K Ota, G Maussion, H Peng, K Vaillancourt, A B Diallo, J P Lopez, L Crapper, C Vasuta, G G Chen, C Ernst
Genes implicated in neurodevelopmental disorders (NDDs) important in cognition and behavior may have convergent function and several cellular pathways have been implicated, including protein translational control, chromatin modification, and synapse assembly and maintenance. Here, we test the convergent effects of methyl-CpG binding domain 5 (MBD5) and special AT-rich binding protein 2 (SATB2) reduced dosage in human neural stem cells (NSCs), two genes implicated in 2q23.1 and 2q33.1 deletion syndromes, respectively, to develop a generalized model for NDDs...
2015: Translational Psychiatry
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