A ceRNA approach may unveil unexpected contributors to deletion syndromes, the model of 5q- syndrome

Abstract

In genomic deletions, gene haploinsufficiency might directly configure a specific disease phenotype. Nevertheless, in some cases no functional association can be identified between haploinsufficient genes and the deletion-associated phenotype. Transcripts can act as microRNA sponges. The reduction of transcripts from the hemizygous region may increase the availability of specific microRNAs, which in turn may exert in-trans regulation of target genes outside the deleted region, eventually contributing to the phenotype. Here we prospect a competing endogenous RNA (ceRNA) approach for the identification of candidate genes target of epigenetic regulation in deletion syndromes.As a model, we analyzed the 5q- myelodysplastic syndrome. Genes in haploinsufficiency within the common 5q deleted region in CD34+ blasts were identified in silico. Using the miRWalk 2.0 platform, we predicted microRNAs whose availability, and thus activity, could be enhanced by the deletion, and performed a genomewide analysis of the genes outside the 5q deleted region that could be targeted by the predicted miRNAs. The analysis pointed to two genes with altered expression in 5q- transcriptome, which have never been related with 5q- before.The prospected approach allows investigating the global transcriptional effect of genomic deletions, possibly prompting discovery of unsuspected contributors in the deletion-associated phenotype. Moreover, it may help in functionally characterizing previously reported unexpected interactions.

Competing Endogenous RNAs, Non-Coding RNAs and Diseases: An Intertwined Story

“…ceRNAs hypothesis offers a conceptual framework to explain part of certain biological responses in syndromes characterized by large chromosomal rearrangements [ 155 ], which is also observed in certain tumor conditions. In the 5q-syndrome, bone marrow hematopoietic cells undergo the loss of the 5q31.1 band, suffering a hematological disorder that could evolve into acute myeloid leukemia.…”

Dissecting the Functional Mechanisms of Somatic Copy-Number Alterations Based on Dysregulated ceRNA Networks across Cancers

“…A ceRNA method was proposed to investigate the global transcriptional effect of genomic deletions. 23 These studies gave us an inspiration that the view of ceRNA networks associated with SCNAs could provide a more direct manner to explore the functional mechanisms of SCNAs. However, the effect of endogenous expression perturbations of ceRNAs caused by SCNAs on ceRNA networks was less explored.…”

How Altered Ribosome Production Can Cause or Contribute to Human Disease: The Spectrum of Ribosomopathies

“…In addition to inherited ribosomopathies, a defect in the gene encoding for a ribosomal protein is also an underlying factor in an acquired myelodysplastic disorder termed 5q deletion (or 5q−) syndrome. This disorder, which is more frequently found in women over 75 years of age, is due to the somatic deletion of the short arm of chromosome 5, leading to macrocytic anemia and erythroid hypoplasia, which may subsequently progress to AML in some patients [ 133 ]. The haploinsufficiency of the RPS14 gene has been identified by means of an RNA interference-based screening as the predominant cause of the myelodysplastic phenotype in 5q− syndrome [ 11 ], indicating that the alteration in the ribosome biogenesis process may also be at the root of acquired disorders.…”

“…It has long been known that the process of ribosome biogenesis is highly deregulated in cancer [ 12 , 13 ], suggesting that a subset of human tumors may also be considered acquired ribosomopathies. Mutations of NPM1 gene encoding the multifunctional ribosome processing factor nucleophosmin have been described as the most frequent mutation in acute myeloid leukemia [ 133 , 134 ]. Whereas mutations of genes encoding for ribosomal proteins have been reported for the first time in pediatric acute lymphoblastic leukemia, where recurrent mutations of RPL10 and RPL5 genes have been found in approximately 10% of all cases [ 135 ].…”