The Detailed 3D Multi-Loop Aggregate/Rosette Chromatin Architecture and Functional Dynamic Organization of the Human and Mouse G
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Aberrant Methylation Underlies Insulin Gene Expression in Human Insulinoma
ARTICLE https://doi.org/10.1038/s41467-020-18839-1 OPEN Aberrant methylation underlies insulin gene expression in human insulinoma Esra Karakose1,6, Huan Wang 2,6, William Inabnet1, Rajesh V. Thakker 3, Steven Libutti4, Gustavo Fernandez-Ranvier 1, Hyunsuk Suh1, Mark Stevenson 3, Yayoi Kinoshita1, Michael Donovan1, Yevgeniy Antipin1,2, Yan Li5, Xiaoxiao Liu 5, Fulai Jin 5, Peng Wang 1, Andrew Uzilov 1,2, ✉ Carmen Argmann 1, Eric E. Schadt 1,2, Andrew F. Stewart 1,7 , Donald K. Scott 1,7 & Luca Lambertini 1,6 1234567890():,; Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insu- linomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing cano- nical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the cano- nical PDX1 enhancer complex, are predicted to drive INS transactivation. 1 From the Diabetes Obesity and Metabolism Institute, The Department of Surgery, The Department of Pathology, The Department of Genetics and Genomics Sciences and The Institute for Genomics and Multiscale Biology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. -
Research Article Characterization, Tissue Expression, and Imprinting Analysis of the Porcine CDKN1C and NAP1L4 Genes
Hindawi Publishing Corporation Journal of Biomedicine and Biotechnology Volume 2012, Article ID 946527, 7 pages doi:10.1155/2012/946527 Research Article Characterization, Tissue Expression, and Imprinting Analysis of the Porcine CDKN1C and NAP1L4 Genes Shun Li,1 Juan Li,1 Jiawei Tian,1 Ranran Dong,1 Jin Wei,1 Xiaoyan Qiu,2 and Caode Jiang2 1 School of Life Science, Southwest University, Chongqing 400715, China 2 College of Animal Science and Technology, Southwest University, Chongqing 400715, China Correspondence should be addressed to Caode Jiang, [email protected] Received 4 August 2011; Revised 25 October 2011; Accepted 15 November 2011 Academic Editor: Andre Van Wijnen Copyright © 2012 Shun Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. CDKN1C and NAP1L4 in human CDKN1C/KCNQ1OT1 imprinted domain are two key candidate genes responsible for BWS (Beckwith-Wiedemann syndrome) and cancer. In order to increase understanding of these genes in pigs, their cDNAs are characterized in this paper. By the IMpRH panel, porcine CDKN1C and NAP1L4 genes were assigned to porcine chromosome 2, closely linked with IMpRH06175 and with LOD of 15.78 and 17.94, respectively. By real-time quantitative RT-PCR and polymorphism-based method, tissue and allelic expression of both genes were determined using F1 pigs of Rongchang and Landrace reciprocal crosses. The transcription levels of porcine CDKN1C and NAP1L4 were significantly higher in placenta than in other neonatal tissues (P<0.01) although both genes showed the highest expression levels in the lung and kidney of one- month pigs (P<0.01). -
Redefining the Specificity of Phosphoinositide-Binding by Human
bioRxiv preprint doi: https://doi.org/10.1101/2020.06.20.163253; this version posted June 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins Nilmani Singh1†, Adriana Reyes-Ordoñez1†, Michael A. Compagnone1, Jesus F. Moreno Castillo1, Benjamin J. Leslie2, Taekjip Ha2,3,4,5, Jie Chen1* 1Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; 2Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205; 3Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218; 4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205; 5Howard Hughes Medical Institute, Baltimore, MD 21205, USA †These authors contributed equally to this work. *Correspondence: [email protected]. bioRxiv preprint doi: https://doi.org/10.1101/2020.06.20.163253; this version posted June 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. ABSTRACT Pleckstrin homology (PH) domains are presumed to bind phosphoinositides (PIPs), but specific interaction with and regulation by PIPs for most PH domain-containing proteins are unclear. Here we employed a single-molecule pulldown assay to study interactions of lipid vesicles with full-length proteins in mammalian whole cell lysates. -
Snps) Distant from Xenobiotic Response Elements Can Modulate Aryl Hydrocarbon Receptor Function: SNP-Dependent CYP1A1 Induction S
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2018/07/06/dmd.118.082164.DC1 1521-009X/46/9/1372–1381$35.00 https://doi.org/10.1124/dmd.118.082164 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:1372–1381, September 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Single Nucleotide Polymorphisms (SNPs) Distant from Xenobiotic Response Elements Can Modulate Aryl Hydrocarbon Receptor Function: SNP-Dependent CYP1A1 Induction s Duan Liu, Sisi Qin, Balmiki Ray,1 Krishna R. Kalari, Liewei Wang, and Richard M. Weinshilboum Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics (D.L., S.Q., B.R., L.W., R.M.W.) and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.K.), Mayo Clinic, Rochester, Minnesota Received April 22, 2018; accepted June 28, 2018 ABSTRACT Downloaded from CYP1A1 expression can be upregulated by the ligand-activated aryl fashion. LCLs with the AA genotype displayed significantly higher hydrocarbon receptor (AHR). Based on prior observations with AHR-XRE binding and CYP1A1 mRNA expression after 3MC estrogen receptors and estrogen response elements, we tested treatment than did those with the GG genotype. Electrophoretic the hypothesis that single-nucleotide polymorphisms (SNPs) map- mobility shift assay (EMSA) showed that oligonucleotides with the ping hundreds of base pairs (bp) from xenobiotic response elements AA genotype displayed higher LCL nuclear extract binding after (XREs) might influence AHR binding and subsequent gene expres- 3MC treatment than did those with the GG genotype, and mass dmd.aspetjournals.org sion. -
Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications
Stem Cell Rev and Rep DOI 10.1007/s12015-016-9662-8 Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications Behnam Ahmadian Baghbaderani 1 & Adhikarla Syama2 & Renuka Sivapatham3 & Ying Pei4 & Odity Mukherjee2 & Thomas Fellner1 & Xianmin Zeng3,4 & Mahendra S. Rao5,6 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract We have recently described manufacturing of hu- help determine which set of tests will be most useful in mon- man induced pluripotent stem cells (iPSC) master cell banks itoring the cells and establishing criteria for discarding a line. (MCB) generated by a clinically compliant process using cord blood as a starting material (Baghbaderani et al. in Stem Cell Keywords Induced pluripotent stem cells . Embryonic stem Reports, 5(4), 647–659, 2015). In this manuscript, we de- cells . Manufacturing . cGMP . Consent . Markers scribe the detailed characterization of the two iPSC clones generated using this process, including whole genome se- quencing (WGS), microarray, and comparative genomic hy- Introduction bridization (aCGH) single nucleotide polymorphism (SNP) analysis. We compare their profiles with a proposed calibra- Induced pluripotent stem cells (iPSCs) are akin to embryonic tion material and with a reporter subclone and lines made by a stem cells (ESC) [2] in their developmental potential, but dif- similar process from different donors. We believe that iPSCs fer from ESC in the starting cell used and the requirement of a are likely to be used to make multiple clinical products. We set of proteins to induce pluripotency [3]. Although function- further believe that the lines used as input material will be used ally identical, iPSCs may differ from ESC in subtle ways, at different sites and, given their immortal status, will be used including in their epigenetic profile, exposure to the environ- for many years or even decades. -
Letters to the Editor J Med Genet: First Published As 10.1136/Jmg.37.3.231 on 1 March 2000
210 Letters Letters to the Editor J Med Genet: first published as 10.1136/jmg.37.3.231 on 1 March 2000. Downloaded from J Med Genet 2000;37:210–212 No evidence of germline PTEN three reasons: somatic mutations have been found in PTEN in prostate tumours; germline mutations in Cowden mutations in familial prostate cancer disease produce a phenotype (although with no evidence of an associated susceptibility to prostate cancer); and PTEN deficient mice exhibit prostate abnormalities. We have therefore screened the Cancer Research Campaign/British EDITOR—Prostate cancer is the second most common Prostate Group (CRC/BPG) UK Familial Prostate Cancer cause of male cancer mortality in the UK.1 Current indica- Study samples for evidence of PTEN mutations. tions are that like many common cancers, prostate cancer The CRC/BPG UK Familial Prostate Cancer Study has has an inherited component.2 Segregation analysis has led collected lymphocyte DNA from 188 subjects from 50 to the proposed model of at least one highly penetrant, prostate cancer families. These families were chosen dominant gene (with an estimated 88% penetrance for because each contained three or more cases of prostate prostate cancer by the age of 85 in the highly susceptible cancer at any age or related sib pairs where at least one man population). Such a gene or genes would account for an was less than 67 (original criterion was 65) years old at estimated 43% of cases diagnosed at less than 55 years.2 diagnosis. In fact, the majority of the clusters consist of One prostate cancer susceptibility locus (HPC1) has been aVected sib pairs, with DNA often only available from reported on 1q24-253 and confirmed by Cooney et al4 and cases. -
Mclean, Chelsea.Pdf
COMPUTATIONAL PREDICTION AND EXPERIMENTAL VALIDATION OF NOVEL MOUSE IMPRINTED GENES A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Chelsea Marie McLean August 2009 © 2009 Chelsea Marie McLean COMPUTATIONAL PREDICTION AND EXPERIMENTAL VALIDATION OF NOVEL MOUSE IMPRINTED GENES Chelsea Marie McLean, Ph.D. Cornell University 2009 Epigenetic modifications, including DNA methylation and covalent modifications to histone tails, are major contributors to the regulation of gene expression. These changes are reversible, yet can be stably inherited, and may last for multiple generations without change to the underlying DNA sequence. Genomic imprinting results in expression from one of the two parental alleles and is one example of epigenetic control of gene expression. So far, 60 to 100 imprinted genes have been identified in the human and mouse genomes, respectively. Identification of additional imprinted genes has become increasingly important with the realization that imprinting defects are associated with complex disorders ranging from obesity to diabetes and behavioral disorders. Despite the importance imprinted genes play in human health, few studies have undertaken genome-wide searches for new imprinted genes. These have used empirical approaches, with some success. However, computational prediction of novel imprinted genes has recently come to the forefront. I have developed generalized linear models using data on a variety of sequence and epigenetic features within a training set of known imprinted genes. The resulting models were used to predict novel imprinted genes in the mouse genome. After imposing a stringency threshold, I compiled an initial candidate list of 155 genes. -
Is Associated with Hypomethylation At
797 ORIGINAL ARTICLE J Med Genet: first published as 10.1136/jmg.40.11.797 on 19 November 2003. Downloaded from Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith–Wiedemann syndrome N Diaz-Meyer, C D Day, K Khatod, E R Maher, W Cooper, W Reik, C Junien, G Graham, E Algar, V M Der Kaloustian, M J Higgins ............................................................................................................................... J Med Genet 2003;40:797–801 Context: Beckwith–Wiedemann syndrome (BWS) arises by several genetic and epigenetic mechanisms affecting the balance of imprinted gene expression in chromosome 11p15.5. The most frequent alteration associated with BWS is the absence of methylation at the maternal allele of KvDMR1, an intronic CpG island within the KCNQ1 gene. Targeted deletion of KvDMR1 suggests that this locus is an imprinting control region (ICR) that regulates multiple genes in 11p15.5. Cell culture based enhancer blocking assays indicate that KvDMR1 may function as a methylation modulated chromatin insulator and/or silencer. See end of article for Objective: To determine the potential consequence of loss of methylation (LOM) at KvDMR1 in the authors’ affiliations ....................... development of BWS. Methods: The steady state levels of CDKN1C gene expression in fibroblast cells from normal individuals, Correspondence to: and from persons with BWS who have LOM at KvDMR1, was determined by both real time quantitative M J Higgins, Department of Cancer Genetics, polymerase chain reaction (qPCR) and ribonuclease protection assay (RPA). Methylation of the CDKN1C Roswell Park Cancer promoter region was assessed by Southern hybridisation using a methylation sensitive restriction Institute, Buffalo, NY endonuclease. 14263, USA; michael.higgins@ Results: Both qPCR and RPA clearly demonstrated a marked decrease (86–93%) in the expression level of roswellpark.org the CDKN1C gene in cells derived from patients with BWS, who had LOM at KvDMR1. -
Goat Anti-ORP5 (OBPH1) Antibody Peptide-Affinity Purified Goat Antibody Catalog # Af1761a
10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 Goat Anti-ORP5 (OBPH1) Antibody Peptide-affinity purified goat antibody Catalog # AF1761a Specification Goat Anti-ORP5 (OBPH1) Antibody - Product Information Application WB Primary Accession Q9H0X9 Other Accession NP_001137535, 114879, 79196 (mouse) Reactivity Human Predicted Mouse, Rat, Dog Host Goat Clonality Polyclonal Concentration 100ug/200ul Isotype IgG Calculated MW 98616 AF1761a (2 µg/ml) staining of human spleen lysate (35 µg protein in RIPA buffer). Primary Goat Anti-ORP5 (OBPH1) Antibody - Additional incubation was 1 hour. Detected by Information chemiluminescence. Gene ID 114879 Goat Anti-ORP5 (OBPH1) Antibody - Other Names Background Oxysterol-binding protein-related protein 5, ORP-5, OSBP-related protein 5, This gene encodes a member of the Oxysterol-binding protein homolog 1, oxysterol-binding protein (OSBP) family, a OSBPL5, KIAA1534, OBPH1, ORP5 group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin Format homology domain and a highly conserved 0.5 mg IgG/ml in Tris saline (20mM Tris C-terminal OSBP-like sterol-binding domain. pH7.3, 150mM NaCl), 0.02% sodium azide, Transcript variants encoding different isoforms with 0.5% bovine serum albumin have been identified. Storage Maintain refrigerated at 2-8°C for up to 6 Goat Anti-ORP5 (OBPH1) Antibody - months. For long term storage store at References -20°C in small aliquots to prevent freeze-thaw cycles. Genome-wide association study of alcohol dependence implicates a region on Precautions chromosome 11. Edenberg HJ, et al. Alcohol Goat Anti-ORP5 (OBPH1) Antibody is for Clin Exp Res, 2010 May. -
Genome-Wide Expression Profiling Establishes Novel Modulatory Roles
Batra et al. BMC Genomics (2017) 18:252 DOI 10.1186/s12864-017-3635-4 RESEARCHARTICLE Open Access Genome-wide expression profiling establishes novel modulatory roles of vitamin C in THP-1 human monocytic cell line Sakshi Dhingra Batra, Malobi Nandi, Kriti Sikri and Jaya Sivaswami Tyagi* Abstract Background: Vitamin C (vit C) is an essential dietary nutrient, which is a potent antioxidant, a free radical scavenger and functions as a cofactor in many enzymatic reactions. Vit C is also considered to enhance the immune effector function of macrophages, which are regarded to be the first line of defence in response to any pathogen. The THP- 1 cell line is widely used for studying macrophage functions and for analyzing host cell-pathogen interactions. Results: We performed a genome-wide temporal gene expression and functional enrichment analysis of THP-1 cells treated with 100 μM of vit C, a physiologically relevant concentration of the vitamin. Modulatory effects of vitamin C on THP-1 cells were revealed by differential expression of genes starting from 8 h onwards. The number of differentially expressed genes peaked at the earliest time-point i.e. 8 h followed by temporal decline till 96 h. Further, functional enrichment analysis based on statistically stringent criteria revealed a gamut of functional responses, namely, ‘Regulation of gene expression’, ‘Signal transduction’, ‘Cell cycle’, ‘Immune system process’, ‘cAMP metabolic process’, ‘Cholesterol transport’ and ‘Ion homeostasis’. A comparative analysis of vit C-mediated modulation of gene expression data in THP-1cells and human skin fibroblasts disclosed an overlap in certain functional processes such as ‘Regulation of transcription’, ‘Cell cycle’ and ‘Extracellular matrix organization’, and THP-1 specific responses, namely, ‘Regulation of gene expression’ and ‘Ion homeostasis’. -
Associated with Spherical Equivalent
Molecular Vision 2016; 22:783-796 <http://www.molvis.org/molvis/v22/783> © 2016 Molecular Vision Received 20 August 2015 | Accepted 12 July 2016 | Published 14 July 2016 Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent Fei Chen,1 Priya Duggal,1 Barbara E.K. Klein,2 Kristine E. Lee,2 Barbara Truitt,3 Ronald Klein,2 Sudha K. Iyengar,3 Alison P. Klein1,4,5 1Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; 2Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH; 4Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; 5Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD Purpose: Ocular refraction is measured in spherical equivalent as the power of the external lens required to focus images on the retina. Myopia (nearsightedness) and hyperopia (farsightedness) are the most common refractive errors, and the leading causes of visual impairment and blindness in the world. The goal of this study is to identify rare and low-frequency variants that influence spherical equivalent. Methods: We conducted variant-level and gene-level quantitative trait association analyses for mean spherical equiva- lent, using data from 1,560 individuals in the Beaver Dam Eye Study. Genotyping was conducted using the Illumina exome array. We analyzed 34,976 single nucleotide variants and 11,571 autosomal genes across the genome, using single-variant tests as well as gene-based tests. Results: Spherical equivalent was significantly associated with five genes in gene-based analysis: PTCHD2 at 1p36.22 (p = 3.6 × 10−7), CRISP3 at 6p12.3 (p = 4.3 × 10−6), NAP1L4 at 11p15.5 (p = 3.6 × 10−6), FSCB at 14q21.2 (p = 1.5 × 10−7), and AP3B2 at 15q25.2 (p = 1.6 × 10−7). -
Comparative Analysis of Sequence Characteristics of Imprinted Genes in Human, Mouse, and Cattle
Mamm Genome (2007) 18:538–547 DOI 10.1007/s00335-007-9039-z Comparative analysis of sequence characteristics of imprinted genes in human, mouse, and cattle Hasan Khatib Æ Ismail Zaitoun Æ Eui-Soo Kim Received: 28 February 2007 / Accepted: 23 May 2007 / Published online: 26 July 2007 Ó Springer Science+Business Media, LLC 2007 Abstract Genomic imprinting is an epigenetic mecha- in agreement with previous reports for human and mouse nism that results in monoallelic expression of genes imprinted regions. Long interspersed nuclear elements depending on parent-of-origin of the allele. Although the (LINEs) and long terminal repeats (LTRs) were found to be conservation of genomic imprinting among mammalian significantly underrepresented in imprinted genes com- species has been widely reported for many genes, there is pared to control genes, contrary to reports on human and accumulating evidence that some genes escape this con- mouse. Of considerable significance was the finding of servation. Most known imprinted genes have been identi- highly conserved tandem repeats in nine of the genes fied in the mouse and human, with few imprinted genes imprinted in all three species. reported in cattle. Comparative analysis of genomic imprinting across mammalian species would provide a powerful tool for elucidating the mechanisms regulating the unique expression of imprinted genes. In this study we Introduction analyzed the imprinting of 22 genes in human, mouse, and cattle and found that in only 11 was imprinting conserved Genomic imprinting is an epigenetic mechanism that across the three species. In addition, we analyzed the results in monoallelic expression of genes depending on occurrence of the sequence elements CpG islands, C + G parent-of-origin of the allele.