DOCSLIB.ORG

Microrna Profiling in Pediatric Pilocytic Astrocytoma Reveals

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Microrna Profiling in Pediatric Pilocytic Astrocytoma Reveals Neuro-Oncology Advance Access published November 15, 2012 Neuro-Oncology doi:10.1093/neuonc/nos269 NEURO-ONCOLOGY MicroRNA profiling in pediatric pilocytic astrocytoma reveals biologically relevant targets, including PBX3, NFIB, and METAP2 Cheng-Ying Ho, Eli Bar, Caterina Giannini, Luigi Marchionni, Matthias A. Karajannis, David Zagzag, David H. Gutmann, Charles G. Eberhart, and Fausto J. Rodriguez Division of Neuropathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland (C.-Y.H., E.B., C.G.E., F.J.R.); Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (C.G.); Downloaded from Cancer Biology Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (L.M.); Division of Pediatric Hematology/Oncology, Department of Pediatrics (M.A.K.); Division of Neuropathology, Department of Pathology, NYU Langone Medical Center, New York, New York (D.Z.); Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (D.H.G.) http://neuro-oncology.oxfordjournals.org/ Pilocytic astrocytoma (PA) is a World HealthOrganization the mRNA and/or protein level in PA included PBX3, grade I glioma that occurs most commonly in children METAP2, and NFIB. A unique miRNA profile exists and young adults. Specific genetic alterations have in PA, compared with brain tissue. These miRNAs and been described in PA, but the pathogenesis remains their targets may play a role in the pathogenesis of PA. poorly understood. We studied microRNA (miRNA) al- terations in a large cohort of patients with PA. A total of Keywords: BRAF, glioma, microRNA, 43 PA, including 35 sporadic grade I PA, 4 neurofibro- neurofibromatosis, pilocytic astrocytoma. matosis-1 (NF1)–associated PA, and 4 PA with pilo- myxoid features, as well as 5 nonneoplastic brain by guest on November 16, 2012 ilocytic astrocytoma (PA) is a World Health controls were examined. BRAF fusion status was as- Organization (WHO) grade I neoplasm represent- sessed in most cases. RNA was examined using the ing the most frequent primary glioma among chil- Agilent Human miRNA Microarray V3 platform. P dren and young adults. Most PAs have an excellent Expression of miRNA subsets was validated using quan- outcome after gross total resection, particularly when titative real-time PCR (qRT-PCR) with Taqman probes. they arise in accessible anatomic locations, such as the Validation of predicted protein targets was performed cerebellum. However, a subset may behave in a more ag- on tissue microarrays with the use of immunohistochem- gressive fashion and clinically progress despite the use of istry. We identified a subset of miRNAs that were differ- conventional treatments. Histologic features associated entially expressed in pediatric PAs versus normal brain with a more aggressive course include the presence of tissue: 13 miRNAs were underexpressed, and 20 monomorphous pilomyxoid features (ie, pilomyxoid miRNAs were overexpressed in tumors. Differences variant)1 and anaplasia in the form of brisk mitotic were validated by qRT-PCR in a subset, with mean activity with or without necrosis.2 fold change in tumor versus brain of -17 (miR-124), Recent studies have highlighted novel genetic alter- -15 (miR-129), and 19.8 (miR-21). Searching for pre- ations associated with PA. Tandem duplications of the dicted protein targets in Targetscan, we identified a BRAF kinase domain, leading to a BRAF:KIAA1549 number of known and putative oncogenes that were pre- fusion, are present in most PAs.3–10 Asubsetoftumors dicted targets of miRNA sets relatively underexpressed have other, usually mutually exclusive alterations, includ- in PA. Predicted targets with increased expression at ing RAF1 rearrangements, a FAM131B-BRAF fusion me- diated by a small interstitial deletion, or small BRAF insertions.10 –12 In addition, PA is the most frequent Received March 22, 2012; accepted September 12, 2012. glioma in patients with neurofibromatosis type 1,13 result- Corresponding Author: Fausto J. Rodriguez, MD, Department of ing from germline mutations in the NF1 gene and homozy- Pathology, Division of Neuropathology, Johns Hopkins Hospital, gous inactivation in associated tumors, leading to RAS Sheikh Zayed Tower, Rm M2101, 1800 Orleans St, Baltimore, MD activation. All these genetic alterations lead to down- 14 21231 ([email protected]). stream activation of the MAPK signaling pathway. # The Author(s) 2012. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected]. Ho et al.: MicroRNA profiles of pilocytic astrocytoma In recent years, an increasing role for noncoding small WHO grade I PAs, 4 NF1-associated PAs, and 4 PAs RNA (ie, microRNA) has been uncovered in carcinogen- with pilomyxoid features. All patients (except for 2) esis. Mature microRNAs are small, single-stranded RNA were ≤18 years of age at the time of surgery (median, molecules that bind to regulatory sequences of key 10 years). Nonneoplastic tissue controls included fetal mRNAs, promoting their degradation and/or inhibiting cerebellum (n ¼ 1) and pediatric cerebellum (n ¼ 1) ob- translation. In the process of carcinogenesis, the upregu- tained by autopsy and cerebral cortex obtained during lation of particular microRNAs may affect tumor sup- seizure surgery (n ¼ 2) or biopsy for a nonspecific neuro- pressors, whereas downregulation may allow logic disorder with gliosis (n ¼ 1). Nine additional overexpression of oncoproteins, resulting in deregula- autopsy-derived cerebellar tissue samples were included tion of cell proliferation and survival. for quantitative real-time polymerase chain reaction Several microRNAs have been shown to be involved in (qRT-PCR) experiments. brain tumorigenesis, including miR-21, miR-7, miR-181a/ Anatomic locations for tumor samples included optic b, miR-221, and miR-222,15 –19 and seem to regulate onco- pathways (n ¼ 10) and supratentorial (n ¼ 11) and genic signaling pathways in diffuse gliomas, such as glio- infratentorial compartments (n ¼ 22). Most tumors blastoma.20,21 PTEN in particular is a key tumor were previously evaluated for BRAF alterations as part suppressor gene frequently inactivated in diffusely infiltrat- of a separate study and by PCR and sequencing as re- ing gliomas and may in fact be targeted, albeit not exclu- ported.7 Tumors were classified as aggressive if they pro- Downloaded from sively, by specific microRNAs, such as miR-21.22 Because gressed significantly within a year despite conventional microRNAs may have .1 target, microRNA profiling therapies or recurred after gross total resections. Five pa- may stratify biological and clinically relevant subgroups tients met these criteria. Patient and tumor data are sum- more accurately than conventional mRNA profiling.23 marized in Table 1. All studies were approved by the Low-grade pediatric gliomas, such as PAs in particular, Johns Hopkins, NYU, and Mayo Clinic Institutional are attractive for microRNA study because they lack Review Boards. http://neuro-oncology.oxfordjournals.org/ gross genomic alterations,24 suggesting that undiscovered epigenetic and subtle genetic changes may contribute to their pathogenesis. In addition, microRNA profiling may MicroRNA Profiling lead to further, biology-based refinements in classifying histopathologically ambiguous low-grade gliomas that Snap frozen fresh tumor tissue samples were used for the defy traditional classification schemes and may have prog- microRNA studies. Sample quality assessment and nostic or therapeutic significance. microarray analyses were performed at the Sidney Because of the low level of genetic instability observed Kimmel Comprehensive Cancer Center Microarray in PAs, we hypothesized that epigenetic or posttranscrip- Core Facility at the Johns Hopkins University tional regulation may play an important role in their (Baltimore, MD). In brief, total RNA was isolated pathogenesis, as described in other low-grade neuroecto- using miRNeasy Mini kits (Qiagen), followed by 25– 27 dermal tumors, such as schwannomas. Some studies quality checks of both total RNA and small RNA with by guest on November 16, 2012 have also highlighted a possible role for microRNAs in use of a 2100 Bioanalyzer and software that detects pediatric brain tumors,28,29 including medulloblastoma 28S and 18S ribosomal RNA ratio, total RNA and ependymoma.30 A small number of PAs have also Integrity Number, and small RNA and miRNA concen- been tested for microRNA levels, which may be differen- trations in the total RNA isolated. Only samples with tially expressed in this tumor type.29 Furthermore, over- adequate total and microRNA were used in the study. expression of specific microRNAs has been observed in Samples were hybridized to a Human miRNA papillary carcinoma of the thyroid, another tumor char- Microarray V3 kit (G4470C, Agilent Technologies) acterized by BRAF aberrations.31 Identification of key platform previously proven to produce reproducible microRNAs also provides a rationale for developing results as described elsewhere.33 This array contains inhibitory RNA strategies for therapeutic purposes in 866 human and 89 human viral microRNAs from patients with cancer.32 In the current study, we investigat- the Sanger database, version 12.0. (http://microrna. ed global microRNA expression in a large series of genet- sanger.ac.uk/sequences/). Each miRNA species is ically characterized PAs, including various pathologic printed 20 times with replicate
Load more

Recommended publications
  • Transcriptional Control of Tissue-Resident Memory T Cell Generation
    Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells.
    [Show full text]
  • Microrna Profiling of Low-Grade Glial and Glioneuronal Tumors Shows An
    Modern Pathology (2017) 30, 204–216 204 © 2017 USCAP, Inc All rights reserved 0893-3952/17 $32.00 MicroRNA profiling of low-grade glial and glioneuronal tumors shows an independent role for cluster 14q32.31 member miR-487b Heather Marion Ames1,4, Ming Yuan1,4, Maria Adelita Vizcaíno1,3, Wayne Yu2 and Fausto J Rodriguez1,2 1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA and 3Department of Cellular and Tissue Biology, Universidad Nacional Autónoma de México, Mexico City, DF, USA Low-grade (WHO I-II) gliomas and glioneuronal tumors represent the most frequent primary tumors of the central nervous system in children. They often have a good prognosis following total resection, however they can create many neurological complications due to mass effect, and may be difficult to resect depending on anatomic location. MicroRNAs have been identified as molecular regulators of protein expression/translation that can repress multiple mRNAs concurrently through base pairing, and have an important role in cancer, including brain tumors. Using the NanoString digital counting system, we analyzed the expression levels of 800 microRNAs in nine low-grade glial and glioneuronal tumor types (n = 45). A set of 61 of these microRNAs were differentially expressed in tumors compared with the brain, and several showed levels varying by tumor type. The expression differences were more accentuated in subependymal giant cell astrocytoma, compared with other groups, and demonstrated the highest degree of microRNA repression validated by RT-PCR, including miR-129-2-3p, miR-219-5p, miR-338-3p, miR-487b, miR-885-5p, and miR-323a-3p.
    [Show full text]
  • Association of Cnvs with Methylation Variation
    www.nature.com/npjgenmed ARTICLE OPEN Association of CNVs with methylation variation Xinghua Shi1,8, Saranya Radhakrishnan2, Jia Wen1, Jin Yun Chen2, Junjie Chen1,8, Brianna Ashlyn Lam1, Ryan E. Mills 3, ✉ ✉ Barbara E. Stranger4, Charles Lee5,6,7 and Sunita R. Setlur 2 Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with gene expression. CNV-mQTLs were enriched for regulatory regions, transcription factor-binding sites (TFBSs), and were involved in long- range physical interactions with associated CpGs. Some CNV-mQTLs were associated with methylation of imprinted genes. Several CNV-mQTLs and/or associated genes were among those previously reported by genome-wide association studies (GWASs). We demonstrate that germline CNVs in the genome are associated with CpG methylation. Our findings suggest that structural variation together with methylation may affect cellular phenotype. npj Genomic Medicine (2020) 5:41 ; https://doi.org/10.1038/s41525-020-00145-w 1234567890():,; INTRODUCTION influence transcript regulation is DNA methylation, which involves The extent of genetic variation that exists in the human addition of a methyl group to cytosine residues within a CpG population is continually being characterized in efforts to identify dinucleotide.
    [Show full text]
  • Motif Selection Using Simulated Annealing Algorithm with Application to Identify Regulatory Elements
    Motif Selection Using Simulated Annealing Algorithm with Application to Identify Regulatory Elements A thesis presented to the faculty of the Russ College of Engineering and Technology of Ohio University In partial fulfillment of the requirements for the degree Master of Science Liang Chen August 2018 © 2018 Liang Chen. All Rights Reserved. 2 This thesis titled Motif Selection Using Simulated Annealing Algorithm with Application to Identify Regulatory Elements by LIANG CHEN has been approved for the Department of Electrical Engineering and Computer Science and the Russ College of Engineering and Technology by Lonnie Welch Professor of Electrical Engineering and Computer Science Dennis Irwin Dean, Russ College of Engineering and Technology 3 Abstract CHEN, LIANG, M.S., August 2018, Computer Science Master Program Motif Selection Using Simulated Annealing Algorithm with Application to Identify Regulatory Elements (106 pp.) Director of Thesis: Lonnie Welch Modern research on gene regulation and disorder-related pathways utilize the tools such as microarray and RNA-Seq to analyze the changes in the expression levels of large sets of genes. In silico motif discovery was performed based on the gene expression profile data, which generated a large set of candidate motifs (usually hundreds or thousands of motifs). How to pick a set of biologically meaningful motifs from the candidate motif set is a challenging biological and computational problem. As a computational problem it can be modeled as motif selection problem (MSP). Building solutions for motif selection problem will give biologists direct help in finding transcription factors (TF) that are strongly related to specific pathways and gaining insights of the relationships between genes.
    [Show full text]
  • Functional Testing of a Human PBX3 Variant in Zebrafish Reveals a Potential Modifier Role in Congenital Heart Defects
    bioRxiv preprint doi: https://doi.org/10.1101/337832; this version posted June 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Functional testing of a human PBX3 variant in zebrafish reveals a potential modifier role in congenital heart defects Gist H. Farr III1, Kimia Imani1,2, Darren Pouv1,2, and Lisa Maves1,3* 1Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA 2University of Washington, Seattle, WA, USA 3Department of Pediatrics, University of Washington, Seattle, WA, USA *Correspondence: [email protected] Keywords: CRISPR-Cas, Genetic variant, Heart, Modifier, Pbx, Zebrafish. 1 bioRxiv preprint doi: https://doi.org/10.1101/337832; this version posted June 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Summary statement Our study provides a novel example of using genome editing in zebrafish to demonstrate how a human DNA sequence variant of unknown significance may contribute to the complex genetics of congenital heart defects. Abstract Whole-genome and whole-exome sequencing efforts are increasingly identifying candidate genetic variants associated with human disease. However, predicting and testing the pathogenicity of a genetic variant remains challenging. Genome editing allows for the rigorous functional testing of human genetic variants in animal models. Congenital heart defects (CHDs) are a prominent example of a human disorder with complex genetics. An inherited sequence variant in the human PBX3 gene (PBX3 p.A136V) has previously been shown to be enriched in a CHD patient cohort, indicating that the PBX3 p.A136V variant could be a modifier allele for CHDs.
    [Show full text]
  • NKX2-5: an Update on This Hypermutable Homeodomain Protein and Its Role in Human Congenital Heart Disease (CHD) Stella Marie Reamon-Buettner, Juergen T Borlak
    NKX2-5: An Update on this Hypermutable Homeodomain Protein and its Role in Human Congenital Heart Disease (CHD) Stella Marie Reamon-Buettner, Juergen T Borlak To cite this version: Stella Marie Reamon-Buettner, Juergen T Borlak. NKX2-5: An Update on this Hypermutable Home- odomain Protein and its Role in Human Congenital Heart Disease (CHD). Human Mutation, Wiley, 2010, 31 (11), pp.1185. 10.1002/humu.21345. hal-00585168 HAL Id: hal-00585168 https://hal.archives-ouvertes.fr/hal-00585168 Submitted on 12 Apr 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Human Mutation NKX2-5: An Update on this Hypermutable Homeodomain Protein and its Role in Human Congenital Heart Disease (CHD) For Peer Review Journal: Human Mutation Manuscript ID: humu-2010-0256.R1 Wiley - Manuscript type: Review Date Submitted by the 15-Jul-2010 Author: Complete List of Authors: Reamon-Buettner, Stella Marie; Fraunhofer Institute of Toxicology and Experimental Medicine, Molecular Medicine and Medical Biotechnology Borlak, Juergen; Fraunhofer Institute of Toxicology and Experimental Medicine, Molecular Medicine and Medical Biotechnology heart development, congenital heart disease, cardiac Key Words: malformations, transcription factors, NKX2-5, mutations John Wiley & Sons, Inc.
    [Show full text]
  • BMC Biology Biomed Central
    BMC Biology BioMed Central Research article Open Access Classification and nomenclature of all human homeobox genes PeterWHHolland*†1, H Anne F Booth†1 and Elspeth A Bruford2 Address: 1Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK and 2HUGO Gene Nomenclature Committee, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK Email: Peter WH Holland* - [email protected]; H Anne F Booth - [email protected]; Elspeth A Bruford - [email protected] * Corresponding author †Equal contributors Published: 26 October 2007 Received: 30 March 2007 Accepted: 26 October 2007 BMC Biology 2007, 5:47 doi:10.1186/1741-7007-5-47 This article is available from: http://www.biomedcentral.com/1741-7007/5/47 © 2007 Holland et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The homeobox genes are a large and diverse group of genes, many of which play important roles in the embryonic development of animals. Increasingly, homeobox genes are being compared between genomes in an attempt to understand the evolution of animal development. Despite their importance, the full diversity of human homeobox genes has not previously been described. Results: We have identified all homeobox genes and pseudogenes in the euchromatic regions of the human genome, finding many unannotated, incorrectly annotated, unnamed, misnamed or misclassified genes and pseudogenes.
    [Show full text]
  • Homeobox Genes and Hepatocellular Carcinoma
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 19 April 2019 doi:10.20944/preprints201904.0224.v1 Peer-reviewed version available at Cancers 2019, 11, 621; doi:10.3390/cancers11050621 1 Review 2 Homeobox genes and hepatocellular carcinoma 3 Kwei-Yan Liu1, Li-Ting Wang1, Shih-Hsien Hsu1,2*, and Shen-Nien Wang 1, 3,4* 4 5 1Graduate Institute of Medicine, College of Medicine; 2 Department of Medical Research, Kaohsiung Medical 6 University Hospital; 3Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical 7 University Hospital; 4Department of Surgery, Faculty of Medicine, Kaohsiung Medical University, Koahiusng 8 807, Taiwan 9 10 *Corresponding Authors: Shih-Hsien Hsu (E-Mail: [email protected]), Graduate Institute of Medicine; 11 Shen-Nien Wang (E-Mail: [email protected]), Department of Surgery, Faculty of Medicine, Kaohsiung 12 Medical University, 807 Kaohsiung, Taiwan. 13 14 Keywords: Homeobox, HCC, EMT, immunosuppression, and IL6 15 16 Abstract 17 Hepatocellular carcinoma (HCC) is the fifth most common type of cancer, and is the third leading cause of 18 cancer-related deaths each year. It involves a multi-step progression and is strongly associated with chronic 19 inflammation induced by the intake of environmental toxins and/or viral infections (i.e., hepatitis B and C 20 viruses). Although several genetic dysregulations are considered to be involved in disease progression, the 21 detailed regulatory mechanisms are not well defined. Homeobox (Hox) genes that encode transcription factors 22 with homeodomains control cell growth, differentiation, and morphogenesis in embryonic development. 23 Recently, more aberrant expressions of Hox genes were found in a wide variety of human cancer, including 24 HCC.
    [Show full text]
  • Pioneer Transcription Factors Are Associated with the Modulation of DNA Methylation Patterns Across Cancers
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.10.443359; this version posted May 10, 2021. 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 4.0 International license. Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers Roza Berhanu Lemma1, Thomas Fleischer2, Emily Martinsen1,3, Vessela N. Kristensen4,5, Ragnhild Eskeland3, Odd Stokke Gabrielsen6, and Anthony Mathelier1,4,* 1 Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway 2 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 3 Institute of Basic Medical Sciences, Department of Molecular Medicine, and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway 4 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway 5 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway 6 Department of Biosciences, University of Oslo, Oslo, Norway. * To whom correspondence should be addressed; email: [email protected] Abstract Methylation of cytosines on DNA is a prominent modification associated with gene expression regulation. Aberrant DNA methylation patterns have recurrently been linked to dysregulation of the regulatory program in cancer cells. To shed light on the underlying molecular mechanism driving this process, we hypothesized that aberrant methylation patterns could be controlled by the binding of specific transcription factors (TFs) across cancer types. By combining DNA methylation arrays and gene expression data with TF binding sites (TFBSs), we explored the interplay between TF binding and DNA methylation in 19 cancer cohorts.
    [Show full text]
  • Cooperation Between Pbx3, Meis1 and Hoxa9 in Leukemia Ross M
    Editorials GD. Plasma factor VIII synthesis and control as revealed by canine currently challenging because of difficulties in accessing organ transplantation. Am J Physiol. 1971;220(5):1147-1154. 4. Everett LA, Cleuren AC, Khoriaty RN, Ginsburg D. Murine coagulation donor tissue, the estimated low yield of residual LSEC, factor VIII is synthesized in endothelial cells. Blood. 2014;123(24):3697- 18 and non-optimized culture systems. However, the grow - 3705. ing field of inducible pluripotent cells may provide useful 5. Fahs SA, Hille MT, Shi Q, Weiler H, Montgomery RR. A conditional alternatives. In addition, LSEC are also attractive for their knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood. ability to induce antigen-specific immune tolerance. 2014;123(24):3706-3713. Lastly, the fact that hepatocyte transplantation does not 6. Shahani T, Covens K, Lavend'homme R, et al. Human liver sinusoidal correct the hemophilia A phenotype in mice may have endothelial cells but not hepatocytes contain factor VIII. J Thromb Haemost. 2014;12(1):36-42. implications for translational studies on liver gene therapy 7. Zanolini D, Merlin S, Feola M, et al. Extrahepatic sources of factor VIII for the disease. To date, the most successful trials for potentially contribute to the coagulation cascade correcting the bleed - hemophilia B are using hepatocyte-specific promoters for ing phenotype of mice with hemophilia A. Haematologica. 2015;100 the expression of factor IX. The fact that factor VIII is not (7):881-892. 8. Follenzi A, Raut S, Merlin S, Sarkar R, Gupta S.
    [Show full text]
  • Plots of Observed and Expected Χ2 Values of Association Between SNP Genotype and Risk of Chronic Lymphocytic Leukemia
    λ = 0.9955 λ = 1.001 a) 60 b) 60 50 50 40 40 values values 2 2 30 30 χ χ 20 20 observed observed 10 10 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 expected χ2 values expected χ2 values λ = 0.9992 λ = 1.1054 c) 60 d) 60 50 50 40 40 values values 2 2 30 30 χ χ 20 20 observed observed 10 10 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 expected χ2 values expected χ2 values λ = 1.0268 λ = 1.0175 e) 60 f) 60 50 50 40 40 values values 2 2 30 30 χ χ 20 20 observed observed 10 10 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 expected χ2 values expected χ2 values Supplementary Figure 1: Quantile-Quantile (Q-Q) plots of observed and expected χ2 values of association between SNP genotype and risk of chronic lymphocytic leukemia. a) UK-CLL1, b) UK-CLL2, c) GEC, d) NHL GWAS, e) UCSF and f) Utah. The red line represents the null hypothesis of no true association. a) rs34676223 Chromosome 1 position (kb, hg19) 23,945 23,950 23,955 23,960 23,965 23,970 23,975 23,980 23,985 Super- CD19+ B-cell enhancers GM12878 MDS2 Genes MDS2 SNPs 4245 _ mCLL 0 _ 3352 _ uCLL ATAC-seq 0 _ 500 _ CD19+ CD20+ B-cell 0 _ 200 _ mCLL H3K27ac 0 _ 200 _ uCLL H3K27ac 0 _ 200 _ Histone mCLL H3K4me1 0 _ marks: 200 _ uCLL CLL H3K4me1 0 _ 50 _ mCLL H3K27me3 0 _ 50 _ uCLL H3K27me3 0 _ 50 _ GM12878 H3K27ac 0 _ Histone 50 _ marks: GM12878 H3K4me1 0 _ GM12878 50 _ GM12878 H3K27me3 0 _ b) rs41271473 Chromosome 1 position (kb, hg19) 228,750 228,800 228,850 228,900 Super- CD19+ B-cell enhancers GM12878 Genes RHOU SNPs 374 _ mCLL 0 _ 316 _ uCLL ATAC-seq 0 _ 200 _ CD19+ CD20+ B-cell 0 _ mCLL 50
    [Show full text]
  • Systematic Discovery and Characterization of Regulatory Motifs in ENCODE TF Binding Experiments Pouya Kheradpour1,2 and Manolis Kellis1,2,*
    Nucleic Acids Research Advance Access published December 13, 2013 Nucleic Acids Research, 2013, 1–12 doi:10.1093/nar/gkt1249 Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments Pouya Kheradpour1,2 and Manolis Kellis1,2,* 1Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA and 2Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02139, USA Received August 7, 2013; Revised November 6, 2013; Accepted November 7, 2013 Downloaded from ABSTRACT present in a given condition and cell type or tissue. As these technologies have matured, their use has become Recent advances in technology have led to a increasingly widespread. The resolution of these experi- dramatic increase in the number of available tran- mental techniques can be as low as 300 bp for ChIP-chip scription factor ChIP-seq and ChIP-chip data sets. (5) and 50 bp for ChIP-seq (6), depending on the experi- Understanding the motif content of these data sets mental design (e.g. fragment size, paired-end sequencing) http://nar.oxfordjournals.org/ is an important step in understanding the underlying and algorithmic processing of the raw data. mechanisms of regulation. Here we provide a sys- The use of these technologies on a variety of factors tematic motif analysis for 427 human ChIP-seq data across many cell types has increasingly highlighted the sets using motifs curated from the literature and complex nature of TF activity, often violating the simple also discovered de novo using five established model of a factor binding to its recognition pattern (motif) motif discovery tools.
    [Show full text]