Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma.

Animals Cell Line, Tumor Disease Models, Animal Gene Expression Regulation Genes, Reporter / genetics Genetic Predisposition to Disease / genetics Genome-Wide Association Study / methods HEK293 Cells Humans Melanocytes / metabolism Melanoma / genetics Mutation Myxovirus Resistance Proteins / genetics Polymorphism, Single Nucleotide Proto-Oncogene Proteins B-raf / genetics Quantitative Trait Loci / genetics Zebrafish / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
01 06 2020
Historique:
received: 06 06 2019
accepted: 12 05 2020
entrez: 3 6 2020
pubmed: 3 6 2020
medline: 18 8 2020
Statut: epublish

Résumé

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAF

Identifiants

DOI: 10.1038/s41467-020-16590-1 PMID: 32483191 PMC: PMC7264232
pubmed: 32483191
doi: 10.1038/s41467-020-16590-1
pii: 10.1038/s41467-020-16590-1
pmc: PMC7264232
doi:

Substances chimiques

MX2 protein, human 0
Myxovirus Resistance Proteins 0
Proto-Oncogene Proteins B-raf EC 2.7.11.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2718

Subventions

Organisme : NCI NIH HHS
ID : R01 CA083115
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA103846
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA010384
Pays : United States
Organisme : Cancer Research UK
ID : C588/A19167
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : R01 HG009120
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163222
Pays : United States

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Auteurs

Jiyeon Choi (J)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
ORCID: 0000-0002-0955-2384

Tongwu Zhang (T)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
ORCID: 0000-0003-2124-2706

Andrew Vu (A)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Julien Ablain (J)

Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
ORCID: 0000-0002-4509-3568

Matthew M Makowski (MM)

Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 XZ, Nijmegen, The Netherlands.

Leandro M Colli (LM)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Mai Xu (M)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Rebecca C Hennessey (RC)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Jinhu Yin (J)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Harriet Rothschild (H)

Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Cathrin Gräwe (C)

Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 XZ, Nijmegen, The Netherlands.

Michael A Kovacs (MA)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Karen M Funderburk (KM)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Myriam Brossard (M)

Université de Paris, UMRS-1124, Institut National de la Santé et de la Recherche Médicale (INSERM), F-75006, Paris, France.
ORCID: 0000-0003-4144-3978

John Taylor (J)

Leeds Institute for Data Analytics, School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
ORCID: 0000-0002-2518-5799

Bogdan Pasaniuc (B)

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90024, USA.

Raj Chari (R)

Genome Modification Core, Frederick National Lab for Cancer Research, National Cancer Institute, Frederick, MD, 21701, USA.

Stephen J Chanock (SJ)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
ORCID: 0000-0002-2324-3393

Clive J Hoggart (CJ)

Department of Medicine, Imperial College London, London, SW7 2BU, UK.

Florence Demenais (F)

Université de Paris, UMRS-1124, Institut National de la Santé et de la Recherche Médicale (INSERM), F-75006, Paris, France.
ORCID: 0000-0001-8361-0936

Jennifer H Barrett (JH)

Leeds Institute for Data Analytics, School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
ORCID: 0000-0002-1720-7724

Matthew H Law (MH)

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
ORCID: 0000-0002-4303-8821

Mark M Iles (MM)

Leeds Institute for Data Analytics, School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
ORCID: 0000-0002-2603-6509

Kai Yu (K)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Michiel Vermeulen (M)

Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 XZ, Nijmegen, The Netherlands.
ORCID: 0000-0003-0836-6894

Leonard I Zon (LI)

Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
ORCID: 0000-0003-0860-926X

Kevin M Brown (KM)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA. kevin.brown3@nih.gov.
ORCID: 0000-0002-8558-6711

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Gènes rapporteurs › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Cellules › Cellules épithéliales › Mélanocytes › Massively parallel reporter assays of melanoma...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Naevus et mélanomes › Mélanome › Massively parallel reporter assays of melanoma...
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