Genes2014, 5(3), 726-738; doi:10.3390/genes5030726 (registering DOI) - published 28 August 2014 Show/Hide Abstract
Abstract: Chronic inflammation due to bacterial overgrowth of the stomach predisposes to the development of gastric cancer and is also associated with high levels of reactive oxygen species (ROS). In recent years increasing attention has been drawn to microRNAs (miRNAs) due to their role in the pathogenesis of many human diseases including gastric cancer. Here we studied the impact of infection by the gram-positive bacteria Enterococcus faecalis (E. faecalis) on global miRNA expression as well as the effect of ROS on selected miRNAs. Human gastric adenocarcinoma cell line MKN74 was infected with living E. faecalis for 24 h or for 5 days or with E. faecalis lysate for 5 days. The miRNA expression was examined by microarray analysis using Affymetrix GeneChip miRNA Arrays. To test the effect of ROS, MKN74 cells were treated with 100 mM tert-Butyl hydroperoxide (TBHP). Following 5 days of E. faecalis infection we found 91 differentially expressed miRNAs in response to living bacteria and 2 miRNAs responded to E. faecalis lysate. We verified the down-regulation of the miR-17-92 and miR-106-363 clusters and of other miRNAs involved in the oxidative stress-response by qRT-PCR. We conclude that only infection by living E. faecalis bacteria caused a significant global response in miRNA expression in the MKN74 cell culture. E. faecalis infection as well as ROS stimulation down-regulated the expression of the miR-17-92 cluster. We believe that these changes could reflect a general response of gastric epithelial cells to bacterial infections.
Abstract: Whole-exome sequencing (WES) is a new tool that allows the rapid, inexpensive and accurate exploration of Mendelian and complex diseases, such as obesity. To identify sequence variants associated with obesity, we performed WES of family trios of one male teenager and one female child with severe early-onset obesity. Additionally, the teenager patient had hypopituitarism and hyperprolactinaemia. A comprehensive bioinformatics analysis found de novo and compound heterozygote sequence variants with a damaging effect on genes previously associated with obesity in mice (LRP2) and humans (UCP2), among other intriguing mutations affecting ciliary function (DNAAF1). A gene ontology and pathway analysis of genes harbouring mutations resulted in the significant identification of overrepresented pathways related to ATP/ITP (adenosine/inosine triphosphate) metabolism and, in general, to the regulation of lipid metabolism. We discuss the clinical and physiological consequences of these mutations and the importance of these findings for either the clinical assessment or eventual treatment of morbid obesity.
Abstract: Polycystic ovary syndrome (PCOS) is the most common, though heterogeneous, endocrine aberration in women of reproductive age, with high prevalence and socioeconomic costs. The syndrome is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism, as well as being associated with infertility, insulin resistance, chronic low-grade inflammation and an increased life time risk of type 2 diabetes. MicroRNAs (miRNAs) are small, non-coding RNAs that are able to regulate gene expression at the post-transcriptional level. Altered miRNA levels have been associated with diabetes, insulin resistance, inflammation and various cancers. Studies have shown that circulating miRNAs are present in whole blood, serum, plasma and the follicular fluid of PCOS patients and that they might serve as potential biomarkers and a new approach for the diagnosis of PCOS. In this review, recent work on miRNAs with respect to PCOS will be summarized. Our understanding of miRNAs, particularly in relation to PCOS, is currently at a very early stage, and additional studies will yield important insight into the molecular mechanisms behind this complex and heterogenic syndrome.
Abstract: MicroRNAs (miRNAs) have been identified as one of the most important molecules that regulate gene expression in various organisms. miRNAs are short, 21–23 nucleotide-long, single stranded RNA molecules that bind to 3' untranslated regions (3' UTRs) of their target mRNAs. In general, they silence the expression of their target genes via degradation of the mRNA or by translational repression. The expression of miRNAs, on the other hand, also varies in different tissues based on their functions. It is significantly important to predict the targets of miRNAs by computational approaches to understand their effects on the regulation of gene expression. Various computational methods have been generated for miRNA target prediction but the resulting lists of candidate target genes from different algorithms often do not overlap. It is crucial to adjust the bioinformatics tools for more accurate predictions as it is equally important to validate the predicted target genes experimentally.
Abstract: Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about by epigenetic and mRNA processing changes, loss of protein homeostasis, altered nutrient signaling, mitochondrial dysfunction, stem cell exhaustion, premature cellular senescence and altered intracellular communication. Like practically all other cellular processes, genes associated in features of ageing are regulated by miRNAs. In this review, I will outline each of the features of ageing, together with examples of specific miRNAs that have been demonstrated to be involved in each one. This will demonstrate the interconnected nature of the regulation of transcripts involved in human ageing, and the role of miRNAs in this process. Definition of the factors involved in degeneration of organismal, tissue and cellular homeostasis may provide biomarkers for healthy ageing and increase understanding of the processes that underpin the ageing process itself.
Abstract: Epigenetic mechanisms modulate genome function by writing, reading and erasing chromatin structural features. These have an impact on gene expression, contributing to the establishment, maintenance and dynamic changes in cellular properties in normal and abnormal situations. Great effort has recently been undertaken to catalogue the genome-wide patterns of epigenetic marks—creating reference epigenomes—which will deepen our understanding of their contributions to genome regulation and function with the promise of revealing further insights into disease etiology. The foundation for these global studies is the smaller scale experimentally-derived observations and questions that have arisen through the study of epigenetic mechanisms in model systems. One such system is genomic imprinting, a process causing the mono-allelic expression of genes in a parental-origin specific manner controlled by a hierarchy of epigenetic events that have taught us much about the dynamic interplay between key regulators of epigenetic control. Here, we summarize some of the most noteworthy lessons that studies on imprinting have revealed about epigenetic control on a wider scale. Specifically, we will consider what these studies have revealed about: the variety of relationships between DNA methylation and transcriptional control; the regulation of important protein-DNA interactions by DNA methylation; the interplay between DNA methylation and histone modifications; and the regulation and functions of long non-coding RNAs.