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

Effect of Yttrium Doping on Structural, Optical and Morphological Properties of ZrO2 Nanoparticles

In this study, pure and Y-doped ZrO2 nanoparticles were prepared by a simple microwave irradiation method. The nanoparticles were characterized by thermogravimetric and differential thermal analysis (TG-DTA), X-ray diffraction (XRD), fourier transform infra-Red spectroscopy (FTIR), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM) and energy dispersive spectrum (EDS). XRD patterns of Y-doped ZrO2 nanoparticles confirmed the cubic structure, while FESEM results showed that the synthesized nanoparticles have polycrystalline nature and spherical morphology. TEM images of pure ZrO2 nanoparticles showed agglomerated spherical nanoparticles with sizes that ranged between 18 and -52 nm; whereas the Y-doped ZrO2 (15 wt%) nanoparticles showed sphere-like shape with sizes in the range of 38 and -64 nm. The optical properties of pure ZrO2 and Y-doped ZrO2 nanoparticles were characterized by UV-Vis diffuse reflectance (DRS) and photoluminescence (PL) spectroscopy

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

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

Normalized density distribution of autism-associated CNVs across human chromosomes.

<p>The normalized CNV density is plotted in y-axis against the chromosomes in x-axis. For any given chromosome, a value above 1 indicates that it has accumulated more number of autism-associated CNVs compared to the mean of all chromosomal CNV densities. The error bars indicate the standard deviation.</p

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

CNV-miRNAs and their target genes involved in the microRNA processing and biogenesis pathways.

<p>Saffron ellipses represent the key components involved in miRNA processing and biogenesis, while miRNAs are denoted by the blue coloured squares. Dashed lines represent the validated interactions between the genes and CNV-miRNAs.</p