Abstract
Retinoblastoma is a rare pediatric tumor of the retina, caused by the homozygous loss of the Retinoblastoma 1 (RB1) tumor suppressor gene. Previous microarray studies have identified changes in the expression profiles of coding genes; however, our understanding of how non-coding genes change in this tumor is absent. This is an important area of research, as in many adult malignancies, non-coding genes including LNC-RNAs are used as biomarkers to predict outcome and/or relapse. To establish a complete and in-depth RNA profile, of both coding and non-coding genes, in Retinoblastoma tumors, we conducted RNA-seq from a cohort of tumors and normal retina controls. This analysis identified widespread transcriptional changes in the levels of both coding and non-coding genes. Unexpectedly, we also found rare RNA fusion products resulting from genomic alterations, specific to Retinoblastoma tumor samples. We then determined whether these gene expression changes, of both coding and non-coding genes, were also found in a completely independent Retinoblastoma cohort. Using our dataset, we then profiled the potential effects of deregulated LNC-RNAs on the expression of neighboring genes, the entire genome, and on mRNAs that contain a putative area of homology. This analysis showed that most deregulated LNC-RNAs do not act locally to change the transcriptional environment, but potentially function to modulate genes at distant sites. From this analysis, we selected a strongly down-regulated LNC-RNA in Retinoblastoma, DRAIC, and found that restoring DRAIC RNA levels significantly slowed the growth of the Y79 Retinoblastoma cell line. Collectively, our work has generated the first non-coding RNA profile of Retinoblastoma tumors and has found that these tumors show widespread transcriptional deregulation.
Highlights
The protein produced from the Retinoblastoma 1 (RB1) tumor suppressor gene, pRB [1], functions as a molecular scaffold, to bind to and repress the activator E2 promoter binding factor (E2F) transcription factors 1-3 (E2F1-3) [2]
In over 95% of cases, the development of this tumor is driven the homozygous deletion of the Retinoblastoma 1 (RB1) tumor suppressor gene, on chromosome 13p14 [1]
We found significant and recurrent changes in both coding and long non-coding RNAs (LNC-RNAs) within the tumors (Figure 1B)
Summary
The protein produced from the Retinoblastoma 1 (RB1) tumor suppressor gene, pRB [1], functions as a molecular scaffold, to bind to and repress the activator E2 promoter binding factor (E2F) transcription factors 1-3 (E2F1-3) [2]. The activator E2F’s bind to the promoters of genes necessary for cell cycle progression [3] and apoptosis and induce their expression [2] In this context, pRB plays a central role in controlling the cell cycle and acts a critical check-point to prevent cells with DNA damage or other abnormal features from continuing to divide [4]. PRB plays a central role in controlling the cell cycle and acts a critical check-point to prevent cells with DNA damage or other abnormal features from continuing to divide [4] This activity has led to the widespread inactivation of the pRB/E2F in cancer cells, and a number of genomic events disrupt pRB function [1, 5] or lead to constitutive phosphorylation, and inactivation pRB [6,7,8,9,10]. Loss of TP53 or the upregulation of negative regulators of p53, including MDMX, is common in Retinoblastoma [21]
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