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.
Highlights
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, on MYC ability to influence the cellular transcriptome
We used RNA sequencing (RNA-seq) data obtained from (i) hT-RPE-MycER cells, an immortalized retinal pigment epithelial cell line expressing the MycER fusion protein [38, 39]; (ii) P493-6 cells, an immortalized B-lymphoblastic cell line carrying a tetracyclin-inducible MYC construct that was shown to be a good model to study MYC-induced lymphomas [40, 41]; and (iii) 91 germinal center (GC) B cell-derived lymphoma samples subjected to RNA-seq in the framework of the International Cancer Genome Consortium project on malignant lymphoma [ICGC MMML-Seq (International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing)], including 16 Burkitt lymphoma (BL), 35 diffuse large B-cell lymphoma (DLBCL), 40 follicular lymphoma (FL), and 4 controls (Table S1)
To identify long noncoding RNAs (lncRNAs) that are both MYC-regulated and -deregulated in BL, we intersected the data coming from the two model cell lines with those obtained from the lymphomas
Summary
MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown These genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. We have here identified a MYC-regulated lncRNA that we named MYC-induced long noncoding RNA (MINCR) that has a strong correlation with MYC expression in cancer. We focused our analysis on an up-regulated transcript showing the highest positive correlation with MYC expression, which we named MYCinduced long noncoding RNA (MINCR). By using RNAi, we show that MINCR knockdown is associated with reduced cellular proliferation in three different cell types In line with this finding, RNA-seq of cells knocked down for MINCR expression showed a significant reduction in the expression of genes functionally important for cell cycle progression
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