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Genomic Imprinting at the Porcine PLAGL1 Locus and the Orthologous Locus in the Human
G C A T T A C G G C A T genes Article Genomic Imprinting at the Porcine PLAGL1 Locus and the Orthologous Locus in the Human Jinsoo Ahn 1 , In-Sul Hwang 2 , Mi-Ryung Park 2, Seongsoo Hwang 2 and Kichoon Lee 1,* 1 Functional Genomics Laboratory, Department of Animal Sciences, The Ohio State University, Columbus, OH 43210, USA; [email protected] 2 Animal Biotechnology Division, National Institute of Animal Science, Rural Development Administration, Wanju, Jeonbuk 55365, Korea; [email protected] (I.-S.H.); [email protected] (M.-R.P.); [email protected] (S.H.) * Correspondence: [email protected]; Tel.: +1-614-688-7963 Abstract: Implementation of genomic imprinting in mammals often results in cis-acting silencing of a gene cluster and monoallelic expression, which are important for mammalian growth and function. Compared with widely documented imprinting status in humans and mice, current understanding of genomic imprinting in pigs is relatively limited. The objectives of this study were to identify DNA methylation status and allelic expression of alternative spliced isoforms at the porcine PLAGL1 locus and assess the conservation of the locus compared to the orthologous human locus. DNA methylome and transcriptome were constructed using porcine parthenogenetic or biparental control embryos. Using methylome, differentially methylated regions between those embryos were identified. Alternative splicing was identified by differential splicing analysis, and monoallelic expression was examined using single nucleotide polymorphism sites. Moreover, topological boundary regions were identified by analyzing CTCF binding sites and compared with the boundary of human orthologous locus. As a result, it was revealed that the monoallelic expression of the PLAGL1 Citation: Ahn, J.; Hwang, I.-S.; Park, M.-R.; Hwang, S.; Lee, K. -
Two Locus Inheritance of Non-Syndromic Midline Craniosynostosis Via Rare SMAD6 and 4 Common BMP2 Alleles 5 6 Andrew T
1 2 3 Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and 4 common BMP2 alleles 5 6 Andrew T. Timberlake1-3, Jungmin Choi1,2, Samir Zaidi1,2, Qiongshi Lu4, Carol Nelson- 7 Williams1,2, Eric D. Brooks3, Kaya Bilguvar1,5, Irina Tikhonova5, Shrikant Mane1,5, Jenny F. 8 Yang3, Rajendra Sawh-Martinez3, Sarah Persing3, Elizabeth G. Zellner3, Erin Loring1,2,5, Carolyn 9 Chuang3, Amy Galm6, Peter W. Hashim3, Derek M. Steinbacher3, Michael L. DiLuna7, Charles 10 C. Duncan7, Kevin A. Pelphrey8, Hongyu Zhao4, John A. Persing3, Richard P. Lifton1,2,5,9 11 12 1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 13 2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA 14 3Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA 15 4Department of Biostatistics, Yale University School of Medicine, New Haven, CT, USA 16 5Yale Center for Genome Analysis, New Haven, CT, USA 17 6Craniosynostosis and Positional Plagiocephaly Support, New York, NY, USA 18 7Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA 19 8Child Study Center, Yale University School of Medicine, New Haven, CT, USA 20 9The Rockefeller University, New York, NY, USA 21 22 ABSTRACT 23 Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2,000 24 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To 25 identify mutations contributing to common non-syndromic midline (sagittal and metopic) 26 craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 27 additional probands. -
Zinc-Finger Protein 471 Suppresses Gastric Cancer Through
Oncogene (2018) 37:3601–3616 https://doi.org/10.1038/s41388-018-0220-5 ARTICLE Zinc-finger protein 471 suppresses gastric cancer through transcriptionally repressing downstream oncogenic PLS3 and TFAP2A 1 1 1 2 1 3 Lei Cao ● Shiyan Wang ● Yanquan Zhang ● Ka-Chun Wong ● Geicho Nakatsu ● Xiaohong Wang ● 1 3 1 Sunny Wong ● Jiafu Ji ● Jun Yu Received: 28 June 2017 / Revised: 23 December 2017 / Accepted: 23 February 2018 / Published online: 3 April 2018 © The Author(s) 2018. This article is published with open access Abstract Zinc-finger protein 471 (ZNF471) was preferentially methylated in gastric cancer using promoter methylation array. The role of ZNF471 in human cancer is unclear. Here we elucidated the functional significance, molecular mechanisms and clinical impact of ZNF471 in gastric cancer. ZNF471 mRNA was silenced in 15 out of 16 gastric cancer cell lines due to promoter hypermethylation. Significantly higher ZNF471 promoter methylation was also observed in primary gastric cancers compared to their adjacent normal tissues (P<0.001). ZNF471 promoter CpG-site hypermethylation correlated with poor 1234567890();,: survival of gastric cancer patients (n = 120, P = 0.001). Ectopic expression of ZNF471 in gastric cancer cell lines (AGS, BGC823, and MKN74) significantly suppressed cell proliferation, migration, and invasion, while it induced apoptosis in vitro and inhibited xenograft tumorigenesis in nude mice. Transcription factor AP-2 Alpha (TFAP2A) and plastin3 (PLS3) were two crucial downstream targets of ZNF471 demonstrated by bioinformatics modeling and ChIP-PCR assays. ZNF471 directly bound to the promoter of TFAP2A and PLS3 and transcriptionally inhibited their expression. TFAP2A and PLS3 showed oncogenic functions in gastric cancer cell lines. -
Structural Basis for the Regulatory Interactions of Proapoptotic Par-4
Cell Death and Differentiation (2017) 24, 1540–1547 Official journal of the Cell Death Differentiation Association OPEN www.nature.com/cdd Structural basis for the regulatory interactions of proapoptotic Par-4 Udaya K Tiruttani Subhramanyam1,2, Jan Kubicek2,3, Ulf B Eidhoff2 and Joerg Labahn*,1,2 Par-4 is a unique proapoptotic protein with the ability to induce apoptosis selectively in cancer cells. The X-ray crystal structure of the C-terminal domain of Par-4 (Par-4CC), which regulates its apoptotic function, was obtained by MAD phasing. Par-4 homodimerizes by forming a parallel coiled-coil structure. The N-terminal half of Par-4CC contains the homodimerization subdomain. This structure includes a nuclear export signal (Par-4NES) sequence, which is masked upon dimerization indicating a potential mechanism for nuclear localization. The heteromeric-interaction models specifically showed that charge interaction is an important factor in the stability of heteromers of the C-terminal leucine zipper subdomain of Par-4 (Par-4LZ). These heteromer models also displayed NES masking capacity and therefore the ability to influence intracellular localization. Cell Death and Differentiation (2017) 24, 1540–1547; doi:10.1038/cdd.2017.76; published online 16 June 2017 Par-4 is a 332 amino-acid proapoptotic protein with tumor mainly shown to mediates the interaction with partner proteins suppressor activity. Par-4 had been predicted to be largely such as PKCζ,15 WT1,16 Akt1,13 apoptosis antagonizing disordered.1 Its downregulation or non-functional state -
New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma
cancers Review New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma Kathy H. Y. Shair 1,2,*, Akhil Reddy 1 and Vaughn S. Cooper 2 ID 1 Cancer Virology Program, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; [email protected] 2 Department of Microbiology and Molecular Genetics, and Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-412-623-7717 Received: 3 March 2018; Accepted: 20 March 2018; Published: 21 March 2018 Abstract: Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in cytosolic membrane compartments, but the effects of LMP1 extend to nuclear and extracellular processes. Although LMP1 is one of the latent genes required for EBV-immortalization of B cells, the biology of LMP1 in the pathogenesis of the epithelial cancer nasopharyngeal carcinoma (NPC) is more complex. NPC is prevalent in specific regions of the world with high incidence in southeast China. The epidemiology and time interval from seroconversion to NPC onset in adults would suggest the involvement of multiple risk factors that complement the establishment of a latent and persistent EBV infection. The contribution of LMP1 to EBV pathogenesis in polarized epithelia has only recently begun to be elucidated. Furthermore, the LMP1 gene has emerged as one of the most divergent sequences in the EBV genome. -
PLAGL1 (ZAC1/LOT1) Expression in Clear Cell Renal Cell Carcinoma: Correlations with Disease Progression and Unfavorable Prognosis
ANTICANCER RESEARCH 36: 617-624 (2016) PLAGL1 (ZAC1/LOT1) Expression in Clear Cell Renal Cell Carcinoma: Correlations with Disease Progression and Unfavorable Prognosis JANUSZ GODLEWSKI1, BARTLOMIEJ E. KRAZINSKI1, ANNA E. KOWALCZYK1, JOLANTA KIEWISZ1, JACEK KIEZUN1, PRZEMYSLAW KWIATKOWSKI1, AGNIESZKA SLIWINSKA-JEWSIEWICKA1, ZBIGNIEW MASLOWSKI2 and ZBIGNIEW KMIEC1,3 1Department of Human Histology and Embryology, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland; 2Department of Oncological Surgery, Warmia and Mazury Oncological Center, Olsztyn, Poland; 3Department of Histology, Medical University of Gdansk, Gdansk, Poland Abstract. Background: Pleiomorphic adenoma gene-like 1 Clear cell renal cell carcinoma (ccRCC), the prevailing form (PLAGL1) protein was originally shown to induce cell-cycle of RCC, is characterized by the most aggressive behavior and arrest and promote apoptosis in several types of human poor prognosis among all types of kidney cancer (1-3). tumors and therefore it was considered a candidate tumor Although ccRCC tumors can be removed surgically, suppressor. The involvement of PLAGL1 gene in the etiology haematogeneous metastases frequently occur in the early and pathogenesis of clear cell renal cell carcinoma (ccRCC) stage of the disease and 35-65% of patients develop has not been evaluated. The purpose of the present study metastatic disease after nephrectomy (3). Over the past was to determine the expression level of PLAGL1 in ccRCC decade, the background of ccRCC pathogenesis has been and to investigate its potential utility as a prognostic factor. extensively screened for molecular biomarkers and relevant Materials and Methods: We applied quantitative real-time gene signatures, however, only few have significant polymerase chain reaction (QPCR), western blotting and prognostic value which can be used in clinical practice (3-5). -
The Complex SNP and CNV Genetic Architecture of the Increased Risk of Congenital Heart Defects in Down Syndrome
Downloaded from genome.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Research The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome M. Reza Sailani,1,2 Periklis Makrythanasis,1 Armand Valsesia,3,4,5 Federico A. Santoni,1 Samuel Deutsch,1 Konstantin Popadin,1 Christelle Borel,1 Eugenia Migliavacca,1 Andrew J. Sharp,1,20 Genevieve Duriaux Sail,1 Emilie Falconnet,1 Kelly Rabionet,6,7,8 Clara Serra-Juhe´,7,9 Stefano Vicari,10 Daniela Laux,11 Yann Grattau,12 Guy Dembour,13 Andre Megarbane,12,14 Renaud Touraine,15 Samantha Stora,12 Sofia Kitsiou,16 Helena Fryssira,16 Chariklia Chatzisevastou-Loukidou,16 Emmanouel Kanavakis,16 Giuseppe Merla,17 Damien Bonnet,11 Luis A. Pe´rez-Jurado,7,9 Xavier Estivill,6,7,8 Jean M. Delabar,18 and Stylianos E. Antonarakis1,2,19,21 1–19[Author affiliations appear at the end of the paper.] Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21–specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). -
© Copyright 2021 Heather Raquel Dahlin
© Copyright 2021 Heather Raquel Dahlin The Structure of Sperm Autoantigenic Protein (SPA17): An R2D2 Protein Critical to Cilia and Implicated in Oncogenesis Heather Raquel Dahlin A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2021 Reading Committee: John D. Scott, Chair Ning Zheng Linda Wordeman Program Authorized to Offer Degree: Pharmacology University of Washington Abstract Structure of SPA17: An R2D2 Protein Critical to Cilia and Implicated in Oncogenesis Heather Raquel Dahlin Chair of the Supervisory Committee: John D. Scott, Ph.D., Edwin G. Krebs- Speights Professor of Cell Signaling and Cancer Biology Pharmacology A-Kinase Anchoring proteins (AKAPs) localize the activity of cyclic AMP (cAMP)-Dependent Protein Kinase (PKA) through interaction of an amphipathic helix that binds to a conserved RIIα docking and dimerization (R2D2) domain on the N-terminus of PKA. Genome analysis indicates that at least thirteen other RIIα superfamily proteins exist in humans, which are not coupled to cyclic nucleotide binding domains and are largely localized to cilia and flagella. The newly reported R2D2 proteins exist in two lineages differing by their similarity to Type I or Type II PKA. Moreover, R2D2 domains bind to AKAPs and can contain extra regulatory sequences conferring novel functions and binding specificity. Here we detail the structure of one such domain comprising the N-terminus of Sperm Autoantigenic Protein 17 (SPA17) resolved to 1.72 Å. The structure of core hydrophobic sites for dimerization and AKAP binding are highly conserved between PKA and SPA17. Additional flanking sequences outside of the core R2D2 domain occlude the AKAP binding site and reduce the affinity for AKAP helices in the absence of heterodimerization with another R2D2 protein, ROPN1L. -
Analysis of the Indacaterol-Regulated Transcriptome in Human Airway
Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/04/13/jpet.118.249292.DC1 1521-0103/366/1/220–236$35.00 https://doi.org/10.1124/jpet.118.249292 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:220–236, July 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the s Adverse and Therapeutic Effects of b2-Adrenoceptor Agonists Dong Yan, Omar Hamed, Taruna Joshi,1 Mahmoud M. Mostafa, Kyla C. Jamieson, Radhika Joshi, Robert Newton, and Mark A. Giembycz Departments of Physiology and Pharmacology (D.Y., O.H., T.J., K.C.J., R.J., M.A.G.) and Cell Biology and Anatomy (M.M.M., R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Received March 22, 2018; accepted April 11, 2018 Downloaded from ABSTRACT The contribution of gene expression changes to the adverse and activity, and positive regulation of neutrophil chemotaxis. The therapeutic effects of b2-adrenoceptor agonists in asthma was general enriched GO term extracellular space was also associ- investigated using human airway epithelial cells as a therapeu- ated with indacaterol-induced genes, and many of those, in- tically relevant target. Operational model-fitting established that cluding CRISPLD2, DMBT1, GAS1, and SOCS3, have putative jpet.aspetjournals.org the long-acting b2-adrenoceptor agonists (LABA) indacaterol, anti-inflammatory, antibacterial, and/or antiviral activity. Numer- salmeterol, formoterol, and picumeterol were full agonists on ous indacaterol-regulated genes were also induced or repressed BEAS-2B cells transfected with a cAMP-response element in BEAS-2B cells and human primary bronchial epithelial cells by reporter but differed in efficacy (indacaterol $ formoterol . -
Paternal Finasteride Treatment Can Influence the Testicular
Article Paternal Finasteride Treatment Can Influence the Testicular Transcriptome Profile of Male Offspring—Preliminary Study Agnieszka Kolasa 1,* , Dorota Rogi ´nska 2 , Sylwia Rzeszotek 1 , Bogusław Machali ´nski 2 and Barbara Wiszniewska 1 1 Department of Histology and Embryology, Pomeranian Medical University (PMU), Powsta´nców Wlkp. 72 Avene, 70-111 Szczecin, Poland; [email protected] (S.R.); [email protected] (B.W.) 2 Department of General Pathology, Pomeranian Medical University, Powsta´nców Wlkp. 72 Avene, 70-111 Szczecin, Poland; [email protected] (D.R.); [email protected] (B.M.) * Correspondence: [email protected]; Tel.: +48-91-466-16-77 Abstract: (1) Background: Hormone-dependent events that occur throughout spermatogenesis during postnatal testis maturation are significant for adult male fertility. Any disturbances in the T/DHT ratio in male progeny born from females fertilized by finasteride-treated male rats (F0:Fin) can result in the impairment of testicular physiology. The goal of this work was to profile the testicular transcriptome in the male filial generation (F1:Fin) from paternal F0:Fin rats. (2) Methods: The subject material for the study were testis from immature and mature male rats born from females fertilized by finasteride-treated rats. Testicular tissues from the offspring were used in microarray analyses. (3) Results: The top 10 genes having the highest and lowest fold change values were mainly those that encoded odoriferous (Olfr: 31, 331, 365, 633, 774, 814, 890, 935, 1109, 1112, 1173, 1251, 1259, 1253, 1383) Citation: Kolasa, A.; Rogi´nska,D.; Vmn1r 50 103 210 211 Vmn2r 3 23 99 RIKEN cDNA 5430402E10 Rzeszotek, S.; Machali´nski,B.; and vomeronasal ( : , , , ; : , , ) receptors and , Wiszniewska, B. -
NOTCH1 Gene Notch 1
NOTCH1 gene notch 1 Normal Function The NOTCH1 gene provides instructions for making a protein called Notch1, a member of the Notch family of receptors. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Attachment of a ligand to the Notch1 receptor sends signals that are important for normal development of many tissues throughout the body, both before birth and after. Notch1 signaling helps determine the specialization of cells into certain cell types that perform particular functions in the body (cell fate determination). It also plays a role in cell growth and division (proliferation), maturation (differentiation), and self-destruction (apoptosis). The protein produced from the NOTCH1 gene has such diverse functions that the gene is considered both an oncogene and a tumor suppressor. Oncogenes typically promote cell proliferation or survival, and when mutated, they have the potential to cause normal cells to become cancerous. In contrast, tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way, preventing the development of cancer; mutations that impair tumor suppressors can lead to cancer development. Health Conditions Related to Genetic Changes Adams-Oliver syndrome At least 15 mutations in the NOTCH1 gene have been found to cause Adams-Oliver syndrome, a condition characterized by areas of missing skin (aplasia cutis congenita), usually on the scalp, and malformations of the hands and feet. These mutations are usually inherited and are present in every cell of the body. Some of the NOTCH1 gene mutations involved in Adams-Oliver syndrome lead to production of an abnormally short protein that is likely broken down quickly, causing a shortage of Notch1. -
Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing