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Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):E5261-70. doi: 10.1073/pnas.1505753112. Epub 2015 Sep 8.

MINCR is a MYC-induced lncRNA able to modulate MYC's transcriptional network in Burkitt lymphoma cells.

Author information

1
Transcriptome Bioinformatics, Leipzig Research Center for Civilization Diseases, University of Leipzig, D-04107 Leipzig, Germany;
2
Institute of Human Genetics, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
3
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich Heine University, Medical Faculty, D-40225 Düsseldorf, Germany;
4
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;
5
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;
6
Department of Pediatrics, University Hospital Schleswig-Holstein, D-24105 Kiel, Germany;
7
Institute of Pathology, Charité University Medicine Berlin, D-12200 Berlin, Germany;
8
Friedrich-Ebert Hospital Neumünster, Clinics for Hematology, Oncology and Nephrology, D-24534 Neumünster, Germany;
9
Department of Internal Medicine II: Hematology and Oncology, University Medical Centre, D-24105 Kiel, Germany;
10
Hematopathology Section, University Hospital Schleswig-Holstein, Christian Albrechts University, D-24105 Kiel, Germany;
11
Institute for Medical Informatics Statistics and Epidemiology, University of Leipzig, D-04107 Leipzig, Germany;
12
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, D-45122 Essen, Germany;
13
Division Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany;
14
Hospital of Internal Medicine II, Hematology and Oncology, St. Georg Hospital Leipzig, D-04129 Leipzig, Germany;
15
Institute of Pathology, Ulm University, D-89070 Ulm, Germany;
16
Department of Clinical Pathology, Robert Bosch Hospital and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany;
17
Department of Pediatric Hematology and Oncology, University Hospital Giessen, D-35392 Giessen, Germany;
18
Institute of Clinical Molecular Biology, Christian Albrechts University, D-24105 Kiel, Germany;
19
Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, D-97080 Würzburg, Germany;
20
Department of Internal Medicine III, University of Ulm, D-89081 Ulm, Germany;
21
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, 6525 Nijmegen, The Netherlands;
22
Department of Hematology and Oncology, Georg August University of Göttingen, D-37075 Göttingen, Germany;
23
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.

Abstract

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.

KEYWORDS:

B-cell lymphoma; MYC; cell cycle; lncRNA

Comment in

PMID:
26351698
PMCID:
PMC4586867
DOI:
10.1073/pnas.1505753112
[Indexed for MEDLINE]
Free PMC Article

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