DOCSLIB.ORG

Identification of Gene Ontologies Linked to Prefrontal–Hippocampal

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of Gene Ontologies Linked to Prefrontal–Hippocampal Retraction and Correction RETRACTION CORRECTION SYSTEMS BIOLOGY CELL BIOLOGY Retraction for “Identification of gene ontologies linked to pre- Correction for “STAT1-induced ASPP2 transcription identifies a frontal–hippocampal functional coupling in the human brain,” by link between neuroinflammation, cell polarity, and tumor sup- Luanna Dixson, Henrik Walter, Michael Schneider, Susanne Erk, pression,” by Casmir Turnquist, Yihua Wang, David T. Severson, Axel Schäfer, Leila Haddad, Oliver Grimm, Manuel Mattheisen, Shan Zhong, Bin Sun, Jingyi Ma, Stefan N. Constaninescu, Olaf Markus M. Nöthen, Sven Cichon, Stephanie H. Witt, Marcella Ansorge, Helen B. Stolp, Zoltán Molnár, Francis G. Szele, and Rietschel, Sebastian Mohnke, Nina Seiferth, Andreas Heinz, Heike Xin Lu, which appeared in issue 27, July 8, 2014, of Proc Natl Tost, and Andreas Meyer-Lindenberg, which appeared in issue 26, Acad Sci USA (111:9834–9839; first published June 23, 2014; July 1, 2014, of Proc Natl Acad Sci USA (111:9657–9662; first 10.1073/pnas.1407898111). published June 16, 2014; 10.1073/pnas.1404082111). The authors note that the author name Constaninescu should The authors wish to note the following: “In this paper we re- instead appear as Constantinescu. The corrected author line ap- port an association of the ‘synapse organization and biogenesis’ pears below. The online version has been corrected. gene set with a neuroimaging phenotype, using gene set en- richment methodology. The methods and results of the paper, as Casmir Turnquist, Yihua Wang, David T. Severson, described, have been conducted after consultation with experts Shan Zhong, Bin Sun, Jingyi Ma, Stefan N. Constantinescu, in the field and support this conclusion. However, a potential Olaf Ansorge, Helen B. Stolp, Zoltán Molnár, confound relating to statistical inference has been brought to our Francis G. Szele, and Xin Lu attention that arises from the fact that several clustered genes, all of which are included in this gene set, have been tagged by the www.pnas.org/cgi/doi/10.1073/pnas.1415682111 same SNP. This problem, which concerns only a small fraction of our tested gene sets (unfortunately including our top finding), belongs to a known category of potential pitfalls in gene set association analyses, and we are sorry that this problem was not detected earlier. Our reanalyses suggest that if adjustments for this confound are applied, the results for our top finding no longer reach experiment-wide significance. Therefore, we feel that the presented findings are not currently sufficiently robust to provide definitive support for the conclusions of our paper, and that an extensive reanalysis of the data is required. The authors have therefore unanimously decided to retract this paper at this time.” Luanna Dixson Henrik Walter Michael Schneider Susanne Erk Axel Schäfer Leila Haddad Oliver Grimm Manuel Mattheisen Markus M. Nöthen Sven Cichon Stephanie H. Witt Marcella Rietschel Sebastian Mohnke Nina Seiferth Andreas Heinz Heike Tost Andreas Meyer-Lindenberg www.pnas.org/cgi/doi/10.1073/pnas.1414905111 13582 | PNAS | September 16, 2014 | vol. 111 | no. 37 www.pnas.org Downloaded by guest on September 26, 2021 Identification of gene ontologies linked to prefrontal– hippocampal functional coupling in the human brain Luanna Dixsona,1, Henrik Walterb,1, Michael Schneidera, Susanne Erkb, Axel Schäfera, Leila Haddada, Oliver Grimma, Manuel Mattheisenc,d,e, Markus M. Nöthenc,d,e, Sven Cichonc,d, Stephanie H. Wittf, Marcella Rietschelf, Sebastian Mohnkeb, Nina Seiferthb, Andreas Heinzb, Heike Tosta,1, and Andreas Meyer-Lindenberga,1,2 Departments of aPsychiatry and Psychotherapy and fGenetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany; bDepartment of Psychiatry, Division of Mind and Brain Research, Charité Campus Mitte, 10117 Berlin, Germany; cDepartment of Genomics, Life and Brain Center, dInstitute of Human Genetics, and eInstitute for Genomic Mathematics, University of Bonn, 53127 Bonn, Germany Edited by Robert Desimone, Massachusetts Institute of Technology, Cambridge, MA, and approved May 16, 2014 (received for review March 5, 2014) Functional interactions between the dorsolateral prefrontal cor- Previous studies have characterized abnormal prefrontal– tex and hippocampus during working memory have been stud- hippocampal interactions in subjects with genetic risk factors for ied extensively as an intermediate phenotype for schizophrenia. schizophrenia (4, 9, 10, 16). In particular, genome-wide associ- Coupling abnormalities have been found in patients, their un- ation studies (GWAS) have become a standard approach for affected siblings, and carriers of common genetic variants associ- identifying common variants that may contribute to risk pheno- ated with schizophrenia, but the global genetic architecture of this types in structural and functional neuroimaging data (10, 16, 17). imaging phenotype is unclear. To achieve genome-wide hypothesis- However, although this approach has been effective in identify- free identification of genes and pathways associated with pre- ing genetic risk variants for imaging phenotypes, post hoc in- frontal–hippocampal interactions, we combined gene set enrich- terpretation of results is challenging. Detected risk variants often ment analysis with whole-genome genotyping and functional fall within intronic sequences, where a lack of prior knowledge magnetic resonance imaging data from 269 healthy German volun- on functionality hinders a mechanistic explanation of how they teers. We found significant enrichment of the synapse organization impact brain function (18). and biogenesis gene set. This gene set included known schizophre- Increasing evidence suggests that common genetic risk variants NRCAM for psychiatric disorders are not distributed randomly but rather SYSTEMS BIOLOGY nia risk genes, such as neural cell adhesion molecule ( )and – calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as lie among sets of genes with overlapping functions (19 22). Gene well as genes with well-defined roles in neurodevelopmental and set enrichment analysis (GSEA) is a data analytical approach that plasticity processes that are dysfunctional in schizophrenia and have leverages a priori knowledge to gain insight into the biological functions of genes and pathways in the analysis of genetic data (23, mechanistic links to prefrontal–hippocampal functional interactions. 24). This approach relies on analysis of sets of genes grouped by Our results demonstrate a readily generalizable approach that can common biological characteristics, such as a shared role in par- be used to identify the neurogenetic basis of systems-level pheno- ticular molecular functions or metabolic pathways. GSEA can then types. Moreover, our findings identify gene sets in which genetic be used to test whether genes that are more strongly associated with variation may contribute to disease risk through altered prefrontal– hippocampal functional interactions and suggest a link to both on- going and developmental synaptic plasticity. Significance functional connectivity | GSEA | endophenotype | genetic risk variants This study combines neuroimaging and whole-genome geno- typing techniques with a gene set enrichment analysis to unravel the genetic basis of a well-validated intermediate maging genetics is widely used to identify neural circuits linked phenotype for schizophrenia, dorsolateral prefrontal cortex– to genetic risk for heritable neuropsychiatric disorders, such as I hippocampal connectivity. We found significant enrichment of schizophrenia, autism, or bipolar disorder (1). A well-established genes with roles in synaptic plasticity and neurodevelopment imaging genetics phenotype is functional connectivity between the that are consistent with the neurobiological basis of pre- right dorsolateral prefrontal cortex (DLPFC) and the left hippo- – – frontal hippocampal interactions in schizophrenia. We further campus (HC) during working memory (WM) performance (2 4). provide additional independent evidence for the intermediate Specifically, impaired interaction of the HC and prefrontal cortex phenotype concept and present a readily generalizable ap- (PFC) has been proposed as a core abnormality during neuro- proach for a biologically driven analysis of imaging and development in schizophrenia. The hippocampus provides input to genetic data. the DLPFC through long-range glutamatergic connections, which have been linked to the glutamate hypothesis of the illness. Author contributions: L.D., H.W., M.S., M.M.N., M.R., A.H., H.T., and A.M.-L. designed Moreover, selective lesions of the hippocampus in primates and research; L.D., H.W., M.S., S.E., A.S., L.H., O.G., M.M., M.M.N., S.C., S.H.W., M.R., S.M., rodents have been shown to result in postpubescent changes in N.S., A.H., H.T., and A.M.-L. performed research; L.D., H.W., M.S., M.M., S.C., S.H.W., H.T., and A.M.-L. analyzed data; and L.D., M.S., H.T., and A.M.-L. wrote the paper. prefrontal regions that are consistent with neuropathological find- Conflict of interest statement: A.M.-L. has received consultant fees and travel expenses ings in schizophrenic patients (5, 6). Brain physiology during WM from Alexza Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Defined Health, Deci- performance is highly heritable (7), and anomalies of prefrontal– sion Resources, Desitin Arzneimittel, Elsevier, F. Hoffmann–La Roche, Gerson Lehrman hippocampal functional
Load more

Recommended publications
  • Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice
    Loyola University Chicago Loyola eCommons Biology: Faculty Publications and Other Works Faculty Publications 2013 Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice Mihaela Palicev Gunter P. Wagner James P. Noonan Benedikt Hallgrimsson James M. Cheverud Loyola University Chicago, [email protected] Follow this and additional works at: https://ecommons.luc.edu/biology_facpubs Part of the Biology Commons Recommended Citation Palicev, M, GP Wagner, JP Noonan, B Hallgrimsson, and JM Cheverud. "Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice." Genome Biology and Evolution 5(10), 2013. This Article is brought to you for free and open access by the Faculty Publications at Loyola eCommons. It has been accepted for inclusion in Biology: Faculty Publications and Other Works by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. © Palicev et al., 2013. GBE Genomic Correlates of Relationship QTL Involved in Fore- versus Hind Limb Divergence in Mice Mihaela Pavlicev1,2,*, Gu¨ nter P. Wagner3, James P. Noonan4, Benedikt Hallgrı´msson5,and James M. Cheverud6 1Konrad Lorenz Institute for Evolution and Cognition Research, Altenberg, Austria 2Department of Pediatrics, Cincinnati Children‘s Hospital Medical Center, Cincinnati, Ohio 3Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University 4Department of Genetics, Yale University School of Medicine 5Department of Cell Biology and Anatomy, The McCaig Institute for Bone and Joint Health and the Alberta Children’s Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Canada 6Department of Anatomy and Neurobiology, Washington University *Corresponding author: E-mail: [email protected].
    [Show full text]
  • Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-Like Mouse Models: Tracking the Role of the Hairless Gene
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2006 Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene Yutao Liu University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Liu, Yutao, "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino- like Mouse Models: Tracking the Role of the Hairless Gene. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1824 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yutao Liu entitled "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich Accepted for the Council: Carolyn R.
    [Show full text]
  • Homeobox Genes Gain Trimethylation of Histone H3 Lysine 4 in Glioblastoma Tissue
    Biosci. Rep. (2016) / 36 / art:e00347 / doi 10.1042/BSR20160028 Homeobox genes gain trimethylation of histone H3 lysine 4 in glioblastoma tissue Kun Luo*1, Donghui Luo† and Hao Wen‡1 *Department of Neurosurgery, Xinjiang Evidence-Based Medicine Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China †Department of Neurology, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China ‡State Key Laboratory Incubation Base of Xinjiang Major Diseases Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China Synopsis Glioblastoma multiforme (GBM) exhibits considerable heterogeneity and associates with genome-wide alterations of the repressed chromatin marks DNA methylation and H3 lysine 27 trimethylation (H3K27me3). Tri-methylation on lysine 4 of histone H3 (H3K4me3) is an activating epigenetic mark that is enriched at promoter and promotes expression. It will be helpful in GBM diagnosis and treatment to identify the alteration of H3K4me3 between human GBM and GBM-surrounding tissues. Here, we performed an analysis using next-generation sequencing techniques to identify H3K4me3 modification in a case of GBM and the GBM-surrounding tissues. The results revealed a global decrease in H3K4me3 in GBM, especially at promoters and CpG islands. In GBM, homeobox genes gain H3K4me3, whereas the cell–cell adhesion-related cadherin genes lose H3K4me3. The products of the homeobox genes are highly connected with Ras-signalling and PI3K-Akt signalling pathways. Using The Cancer Genome Atlas (TCGA) data, we inferred the homeobox-regulated genes’ expression is higher in 548 GBM cases than in 27 lower grade glioma cases giving that OLIG2 expression can be a reference.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Learning from Cadherin Structures and Sequences: Affinity Determinants and Protein Architecture
    Learning from cadherin structures and sequences: affinity determinants and protein architecture Klára Fels ıvályi Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Klara Felsovalyi All rights reserved ABSTRACT Learning from cadherin structures and sequences: affinity determinants and protein architecture Klara Felsovalyi Cadherins are a family of cell-surface proteins mediating adhesion that are important in development and maintenance of tissues. The family is defined by the repeating cadherin domain (EC) in their extracellular region, but they are diverse in terms of protein size, architecture and cellular function. The best-understood subfamily is the type I classical cadherins, which are found in vertebrates and have five EC domains. Among the five different type I classical cadherins, the binding interactions are highly specific in their homo- and heterophilic binding affinities, though their sequences are very similar. As previously shown, E- and N-cadherins, two prototypic members of the subfamily, differ in their homophilic K D by about an order of magnitude, while their heterophilic affinity is intermediate. To examine the source of the binding affinity differences among type I cadherins, we used crystal structures, analytical ultracentrifugation (AUC), surface plasmon resonance (SPR), and electron paramagnetic resonance (EPR) studies. Phylogenetic analysis and binding affinity behavior show that the type I cadherins can be further divided into two subgroups, with E- and N-cadherin representing each. In addition to the affinity differences in their wild-type binding through the strand-swapped interface, a second interface also shows an affinity difference between E- and N-cadherin.
    [Show full text]
  • Acceleration in the DNA Methylation Age in Breast Cancer Tumours from Very Young Women Sara S
    www.nature.com/scientificreports OPEN Acceleration in the DNA methylation age in breast cancer tumours from very young women Sara S. Oltra1, Maria Peña-Chilet1, Kirsty Flower2, María Teresa Martinez1, Elisa Alonso3, Octavio Burgues3, Ana Lluch1,4, James M. Flanagan 2 & Gloria Ribas1,4* Breast cancer in very young women (≤35 years; BCVY) presents more aggressive and complex biological features than their older counterparts (BCO). Our aim was to evaluate methylation diferences between BCVY and BCO and their DNA epigenetic age. EPIC and 450k Illumina methylation arrays were used in 67 breast cancer tumours, including 32 from BCVY, for methylation study and additionally we analysed their epigenetic age. We identifed 2 219 CpG sites diferently-methylated in BCVY vs. BCO (FDR < 0.05; β-value diference ± 0.1). The signature showed a general hypomethylation profle with a selective small hypermethylation profle located in open-sea regions in BCVY against BCO and normal tissue. Strikingly, BCVY presented a signifcant increased epigenetic age-acceleration compared with older women. The afected genes were enriched for pathways in neuronal-system pathways, cell communication, and matrix organisation. Validation in an independent sample highlighted consistent higher expression of HOXD9, and PCDH10 genes in BCVY. Regions implicated in the hypermethylation profle were involved in Notch signalling pathways, the immune system or DNA repair. We further validated HDAC5 expression in BCVY. We have identifed a DNA methylation signature that is specifc to BCVY and have shown that epigenetic age-acceleration is increased in BCVY. Breast cancer (BC) is the most common malignancy in women worldwide1. Approximately 6.6% of BCs are diag- nosed in women aged 40 or younger, and of all cancers diagnosed in this age group, 40% are BCs; the average risk of developing BC by age 40 is one in 1732 and unfortunately, they are not included in mammography screening programmes.
    [Show full text]
  • LETTER Doi:10.1038/Nature09515
    LETTER doi:10.1038/nature09515 Distant metastasis occurs late during the genetic evolution of pancreatic cancer Shinichi Yachida1*, Siaˆn Jones2*, Ivana Bozic3, Tibor Antal3,4, Rebecca Leary2, Baojin Fu1, Mihoko Kamiyama1, Ralph H. Hruban1,5, James R. Eshleman1, Martin A. Nowak3, Victor E. Velculescu2, Kenneth W. Kinzler2, Bert Vogelstein2 & Christine A. Iacobuzio-Donahue1,5,6 Metastasis, the dissemination and growth of neoplastic cells in an were present in the primary pancreatic tumours from which the meta- organ distinct from that in which they originated1,2, is the most stases arose. A small number of these samples of interest were cell lines common cause of death in cancer patients. This is particularly true or xenografts, similar to the index lesions, whereas the majority were for pancreatic cancers, where most patients are diagnosed with fresh-frozen tissues that contained admixed neoplastic, stromal, metastatic disease and few show a sustained response to chemo- inflammatory, endothelial and normal epithelial cells (Fig. 1a). Each therapy or radiation therapy3. Whether the dismal prognosis of tissue sample was therefore microdissected to minimize contaminat- patients with pancreatic cancer compared to patients with other ing non-neoplastic elements before purifying DNA. types of cancer is a result of late diagnosis or early dissemination of Two categories of mutations were identified (Fig. 1b). The first and disease to distant organs is not known. Here we rely on data gen- largest category corresponded to those mutations present in all samples erated by sequencing the genomes of seven pancreatic cancer meta- from a given patient (‘founder’ mutations, mean of 64%, range 48–83% stases to evaluate the clonal relationships among primary and of all mutations per patient; Fig.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Metastatic Adrenocortical Carcinoma Displays Higher Mutation Rate and Tumor Heterogeneity Than Primary Tumors
    ARTICLE DOI: 10.1038/s41467-018-06366-z OPEN Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors Sudheer Kumar Gara1, Justin Lack2, Lisa Zhang1, Emerson Harris1, Margaret Cam2 & Electron Kebebew1,3 Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is 1234567890():,; unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37–57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs. 1 Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 2 Center for Cancer Research, Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 3 Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA. Correspondence and requests for materials should be addressed to E.K. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:4172 | DOI: 10.1038/s41467-018-06366-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06366-z drenocortical carcinoma (ACC) is a rare malignancy with types including primary ACC from the TCGA to understand our A0.7–2 cases per million per year1,2.
    [Show full text]
  • PSD-95 Binding Dynamically Regulates NLGN1 Trafficking and Function
    PSD-95 binding dynamically regulates NLGN1 trafficking and function Jaehoon Jeonga, Saurabh Pandeya, Yan Lia, John D. Badger IIa, Wei Lua, and Katherine W. Rochea,1 aNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 3, 2019 (received for review December 20, 2018) PSD-95 is a scaffolding protein that regulates the synaptic localization necessary for maintaining presynaptic release probability (15). of many receptors, channels, and signaling proteins. The NLGN gene Meanwhile, synaptic targeting of NLGN1 is known to be in- family encodes single-pass transmembrane postsynaptic cell adhesion dependent of PSD-95, as PSD-95 is recruited to the plasma molecules that are important for synapse assembly and function. At membrane after NLGN1 (13, 16, 17). In addition, non-PDZ excitatory synapses, NLGN1 mediates transsynaptic binding with ligand-dependent NLGN1 and NLGN3 functions have been in- neurexin, a presynaptic cell adhesion molecule, and also binds to vestigated (18), suggesting a complicated physiological interplay PSD-95, although the relevance of the PSD-95 interaction is not clear. between NLGNs and PSD-95. We now show that disruption of the NLGN1 and PSD-95 interaction Posttranslational modifications have been reported for several decreases surface expression of NLGN1 in cultured neurons. Further- NLGN isoforms and are postulated to confer distinct properties (11, more, PKA phosphorylates NLGN1 on S839, near the PDZ ligand, and 12). For example, phosphorylation of the cytoplasmic region of dynamically regulates PSD-95 binding. A phosphomimetic mutation NLGN1 has recently emerged as a mechanism for isoform-specific of NLGN1 S839 significantly reduced PSD-95 binding.
    [Show full text]
  • 1 Self-Maintaining Gut Macrophages Are Essential for Intestinal
    Self-maintaining Gut Macrophages Are Essential for Intestinal Homeostasis De Schepper Sebastiaan1*, Verheijden Simon1*†, Aguilera-Lizarraga Javi1, Viola Maria Francesca1, Boesmans Werend2, Stakenborg Nathalie1, Voytyuk Iryna3, Smidt Inga3, Boeckx Bram4,5, Dierckx de Casterlé Isabelle6, Baekelandt Veerle7, Gonzalez Dominguez Erika1, Mack Matthias8, Depoortere Inge9, De Strooper Bart3, Sprangers Ben4, Himmelreich Uwe10, Soenen Stefaan10, Guilliams Martin11, Vanden Berghe Pieter2, Jones Elizabeth12, Lambrechts Diether5,6, Boeckxstaens Guy1 1Laboratory for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Leuven, Belgium. 2Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Leuven, Belgium. 3VIB – KU Leuven Center for Brain and Disease Research, Leuven, Belgium. 4VIB Center for Cancer Biology, Leuven, Belgium. 5Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium. 6Laboratory of Experimental Transplantation, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium. 7Research Group for Neurobiology and Gene Therapy, Department of Neurosciences, University of Leuven, Leuven, Belgium. 8Department of Internal Medicine – Nephrology, University Hospital Regensburg, Regensburg, Germany. 9Gut Peptide Research Lab, Translational
    [Show full text]
  • Autism-Associated Mir-873 Regulates ARID1B, SHANK3 and NRXN2
    Lu et al. Translational Psychiatry (2020) 10:418 https://doi.org/10.1038/s41398-020-01106-8 Translational Psychiatry ARTICLE Open Access Autism-associated miR-873 regulates ARID1B, SHANK3 and NRXN2 involved in neurodevelopment Jing Lu 1, Yan Zhu 1, Sarah Williams2, Michelle Watts 3,MaryA.Tonta1, Harold A. Coleman1, Helena C. Parkington1 and Charles Claudianos 1,4 Abstract Autism spectrum disorders (ASD) are highly heritable neurodevelopmental disorders with significant genetic heterogeneity. Noncoding microRNAs (miRNAs) are recognised as playing key roles in development of ASD albeit the function of these regulatory genes remains unclear. We previously conducted whole-exome sequencing of Australian families with ASD and identified four novel single nucleotide variations in mature miRNA sequences. A pull-down transcriptome analysis using transfected SH-SY5Y cells proposed a mechanistic model to examine changes in binding affinity associated with a unique mutation found in the conserved ‘seed’ region of miR-873-5p (rs777143952: T > A). Results suggested several ASD-risk genes were differentially targeted by wild-type and mutant miR-873 variants. In the current study, a dual-luciferase reporter assay confirmed miR-873 variants have a 20-30% inhibition/dysregulation effect on candidate autism risk genes ARID1B, SHANK3 and NRXN2 and also confirmed the affected expression with qPCR. In vitro mouse hippocampal neurons transfected with mutant miR-873 showed less morphological complexity and enhanced sodium currents and excitatory neurotransmission compared to cells transfected with wild-type miR- 873. A second in vitro study showed CRISPR/Cas9 miR-873 disrupted SH-SY5Y neuroblastoma cells acquired a neuronal-like morphology and increased expression of ASD important genes ARID1B, SHANK3, ADNP2, ANK2 and CHD8.
    [Show full text]