Haploinsufficiency of Tumor Suppressor Genes is Driven by the Cumulative Effect of microRNAs, microRNA Binding Site Polymorphisms and microRNA Polymorphisms: An in silico Approach

Haploinsufficiency of tumor suppressor genes, wherein the reduced production and activity of proteins results in the inability of the cell to maintain normal cellular function, is one among the various causes of cancer. However the precise molecular mechanisms underlying this condition remain unclear. Here we hypothesize that single nucleotide polymorphisms (SNPs) in the 3′untranslated region (UTR) of mRNAs and microRNA seed sequence (miR-SNPs) may cause haploinsufficiency at the level of proteins through altered binding specificity of microRNAs (miRNAs). Bioinformatics analysis of haploinsufficient genes for variations in their 3′UTR showed that the occurrence of SNPs result in the creation of new binding sites for miRNAs, thereby bringing the respective mRNA variant under the control of more miRNAs. In addition, 19 miR-SNPs were found to result in non-specific binding of microRNAs to tumor suppressors. Networking analysis suggests that the haploinsufficient tumor suppressor genes strongly interact with one another, and any subtle alterations in this network will contribute to tumorigenesis

Gliomas: Genetic alterations, mechanisms of metastasis, recurrence, drug resistance, and recent trends in molecular therapeutic options

Glioma is the most common intracranial tumor with poor treatment outcomes and has high morbidity and mortality. Various studies on genomic analyses of glioma found a variety of deregulated genes with somatic mutations including TERT, TP53, IDH1, ATRX, TTN, etc. The genetic alterations in the key genes have been demonstrated to play a crucial role in gliomagenesis by modulating important signaling pathways that alter the fundamental intracellular functions such as DNA damage and repair, cell proliferation, metabolism, growth, wound healing, motility, etc. The SPRK1, MMP2, MMP9, AKT, mTOR, etc., genes, and noncoding RNAs (miRNAs, lncRNAs, circRNAs, etc.) were shown mostly to be implicated in the metastases of glioma. Despite advances in the current treatment strategies, a low-grade glioma is a uniformly fatal disease with overall median survival of ∼ 5-7 years while the patients bearing high-grade tumors display poorer median survival of ∼ 9-10 months mainly due to aggressive metastasis and therapeutic resistance. This review discusses the spectrum of deregulated genes, molecular and cellular mechanisms of metastasis, recurrence, and its management, the plausible causes for the development of therapy resistance, current treatment options, and the recent trends in malignant gliomas. Understanding the pathogenic mechanisms and advances in molecular genetics would aid in the novel diagnosis, prognosis, and translation of pathogenesis-based treatment opportunities which could pave the way for precision medicine in glioma

CNV-microRNA-target genes interaction network in autism.

<p>Saffron ellipses represent the target genes of miRNAs present in the CNV loci, while miRNAs are denoted by the blue coloured squares. Dashed blue lines represent the predicted interactions and solid black edges represent the validated interactions.</p

The genetic heterogeneity model of ASD.

<p>This figure summarizes the various mechanisms by which the dosage of critical genes involved in autism may be altered thereby contributing to the genetic heterogeneity. To elaborate, individual 1 may harbor CNVs that may cause deletion or duplication of a particular miRNA. In individual 2, the target gene(s) present in the CNV regions might show inverse correlation with the deletion/duplication status of the miRNAs altered in individual 1. In individual 3, some genes may be inactivated by mutation or promoter methylation and certain genes may be over expressed due to loss of miRNA control or increased transcriptional activity. Altered expression of miRNAs may directly affect a transcription factor which in-turn may control the downstream genes, with the phenotypic effect reducing down to those mentioned above.</p

Different modes of repression of target genes caused by miRNAs.

<p>A miRNA can directly repress its target genes or can repress the TF that governs the expression of the miRNA’s targets. In addition, the miRNA can repress the TF as well as its target genes thereby having dual effect on repression of the downstream target genes.</p

Insights on the Functional Impact of MicroRNAs Present in Autism-Associated Copy Number Variants

<div><p>Autism spectrum disorder is a complex neurodevelopmental disorder that appears during the first three years of infancy and lasts throughout a person’s life. Recently a large category of genomic structural variants, denoted as copy number variants (CNVs), were established to be a major contributor of the pathophysiology of autism. To date almost all studies have focussed only on the genes present in the CNV loci, but the impact of non-coding regulatory microRNAs (miRNAs) present in these regions remain largely unexplored. Hence we attempted to elucidate the biological and functional significance of miRNAs present in autism-associated CNV loci and their target genes by using a series of computational tools. We demonstrate that nearly 11% of the CNV loci harbor miRNAs and a few of these miRNAs were previously reported to be associated with autism. A systematic analysis of the CNV-miRNAs based on their interactions with the target genes enabled the identification of top 10 miRNAs namely hsa-miR-590-3p, hsa-miR-944, hsa-miR-570, hsa-miR-34a, hsa-miR-124, hsa-miR-548f, hsa-miR-429, hsa-miR-200b, hsa-miR-195 and hsa-miR-497 as hub molecules. Further, the CNV-miRNAs formed a regulatory loop with transcription factors and their downstream target genes, and annotation of these target genes indicated their functional involvement in neurodevelopment and synapse. Moreover, miRNAs present in deleted and duplicated CNV loci may explain the difference in dosage of the crucial genes controlled by them. These CNV-miRNAs can also impair the global processing and biogenesis of all miRNAs by targeting key molecules in the miRNA pathway. To our knowledge, this is the first report to highlight the significance of CNV-microRNAs and their target genes to contribute towards the genetic heterogeneity and phenotypic variability of autism.</p> </div

Functional annotation of the 326 genes targeted by miRNAs present in autism-associated CNV loci.

<p>The results for each enriched GO categories of the 326 genes targeted by the autism associated CNV-miRNAs are listed in this table. Each GO category belongs to one of the three sub-roots (<i>biological process, molecular function, or cellular component</i>). R is the ratio of enrichment. Adj P – P-value adjusted by multiple testing.</p

The genomic location of autism-associated CNV-microRNAs.

<p>The genomic locations of miRNAs present in the 41 CNV loci consistently associated with autism are indicated with arrow heads. The miRNAs labelled in red, green and black indicate the deleted, duplicated and deleted-duplicated categories, respectively.</p

The top 10 hub molecules in the autism CNV-microRNA-target gene network.

*<p>Only selected targets are shown. For the complete list of target genes, see supporting information <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056781#pone.0056781.s005" target="_blank">Table S5</a>.</p