MINCR is a MYC-induced lncRNA able to modulate MYC's transcriptional network in Burkitt lymphoma cells.
Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.
Transcriptome Bioinformatics, Leipzig Research Center for Civilization Diseases, University of Leipzig, D-04107 Leipzig, Germany;
Gero
G
Doose
Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
Andrea
A
Haake
Transcriptome Bioinformatics, Leipzig Research Center for Civilization Diseases, University of Leipzig, D-04107 Leipzig, Germany;
Stephan H
SH
Bernhart
Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
Cristina
C
López
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich Heine University, Medical Faculty, D-40225 Düsseldorf, Germany;
Sujitha
S
Duggimpudi
Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
Franziska
F
Wojciech
Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany; Department of Pediatrics, University Hospital Schleswig-Holstein, D-24105 Kiel, Germany;
Anke K
AK
Bergmann
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich Heine University, Medical Faculty, D-40225 Düsseldorf, Germany;
Arndt
A
Borkhardt
Department of Pediatric Hematology and Oncology, University Hospital Münster, D-48149 Munster, Germany; Department of Pediatric Hematology and Oncology, University Hospital Giessen, D-35392 Giessen, Germany;
Birgit
B
Burkhardt
Department of Pediatrics, University Hospital Schleswig-Holstein, D-24105 Kiel, Germany;
Alexander
A
Claviez
Institute of Pathology, Charité University Medicine Berlin, D-12200 Berlin, Germany;
Lora
L
Dimitrova
Friedrich-Ebert Hospital Neumünster, Clinics for Hematology, Oncology and Nephrology, D-24534 Neumünster, Germany;
Siegfried
S
Haas
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich Heine University, Medical Faculty, D-40225 Düsseldorf, Germany;
Jessica I
JI
Hoell
Institute of Pathology, Charité University Medicine Berlin, D-12200 Berlin, Germany;
Michael
M
Hummel
Department of Internal Medicine II: Hematology and Oncology, University Medical Centre, D-24105 Kiel, Germany;
Dennis
D
Karsch
Hematopathology Section, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
Wolfram
W
Klapper
Institute of Pathology, Charité University Medicine Berlin, D-12200 Berlin, Germany;
Karsten
K
Kleo
Transcriptome Bioinformatics, Leipzig Research Center for Civilization Diseases, University of Leipzig, D-04107 Leipzig, Germany;
Helene
H
Kretzmer
Institute for Medical Informatics Statistics and Epidemiology, University of Leipzig, D-04107 Leipzig, Germany;
Markus
M
Kreuz
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, D-45122 Essen, Germany;
Ralf
R
Küppers
Division Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany;
Chris
C
Lawerenz
Institute of Pathology, Charité University Medicine Berlin, D-12200 Berlin, Germany;
Dido
D
Lenze
Institute for Medical Informatics Statistics and Epidemiology, University of Leipzig, D-04107 Leipzig, Germany;
Markus
M
Loeffler
Hospital of Internal Medicine II, Hematology and Oncology, St. Georg Hospital Leipzig, D-04129 Leipzig, Germany;
Luisa
L
Mantovani-Löffler
Institute of Pathology, Ulm University, D-89070 Ulm, Germany;
Peter
P
Möller
Department of Clinical Pathology, Robert Bosch Hospital and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany;
German
G
Ott
Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
Julia
J
Richter
Department of Pediatric Hematology and Oncology, University Hospital Giessen, D-35392 Giessen, Germany;
Marius
M
Rohde
Institute of Clinical Molecular Biology, Christian Albrechts University, D-24105 Kiel, Germany;
Philip
P
Rosenstiel
Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, D-97080 Würzburg, Germany;
Andreas
A
Rosenwald
Institute of Clinical Molecular Biology, Christian Albrechts University, D-24105 Kiel, Germany;
Markus
M
Schilhabel
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, D-45122 Essen, Germany;
Markus
M
Schneider
Division Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany;
Ingrid
I
Scholz
Department of Internal Medicine III, University of Ulm, D-89081 Ulm, Germany;
Stephan
S
Stilgenbauer
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, 6525 Nijmegen, The Netherlands;
Hendrik G
HG
Stunnenberg
Hematopathology Section, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
Monika
M
Szczepanowski
Department of Hematology and Oncology, Georg August University of Göttingen, D-37075 Göttingen, Germany;
Lorenz
L
Trümper
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, D-45122 Essen, Germany;
Marc A
MA
Weniger
Transcriptome Bioinformatics, Leipzig Research Center for Civilization Diseases, University of Leipzig, D-04107 Leipzig, Germany;
Steve
S
Hoffmann
Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
Reiner
R
Siebert
Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany; Institute of Genetics and Biophysics "A.Buzzati-Traverso," Consiglio Nazionale delle Ricerche, I-80131 Naples, Italy iiaccarino@medgen.uni-kiel.de.
Ingram
I
Iaccarino
D001483:Base Sequence; D001665:Binding Sites; D002051:Burkitt Lymphoma / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
D002843:Chromatin; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; C000621387:long non-coding RNA MINCR, human
B-cell lymphoma; MYC; cell cycle; lncRNA