Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy

MicroRNAs (miRNAs) are short endogenous RNAs known to post-transcriptionally repress gene expression in animals and plants. A microarray profiling survey revealed the expression patterns of 175 human miRNAs across 24 different human organs. Our results show that proximal pairs of miRNAs are generally coexpressed. In addition, an abrupt transition in the correlation between pairs of expressed miRNAs occurs at a distance of 50 kb, implying that miRNAs separated by <50 kb typically derive from a common transcript. Some microRNAs are within the introns of host genes. Intronic miRNAs are usually coordinately expressed with their host gene mRNA, implying that they also generally derive from a common transcript, and that in situ analyses of host gene expression can be used to probe the spatial and temporal localization of intronic miRNAs.

DNA methylation constitutes the most stable type of epigenetic modifications modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation reference profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of 6 annotation categories, revealed evolutionary conserved regions to be the predominant sites for differential DNA methylation and a core region surrounding the transcriptional start site as informative surrogate for promoter methylation. We find 17% of the 873 analyzed genes differentially methylated in their 5′-untranslated regions (5′-UTR) and about one third of the differentially methylated 5′-UTRs to be inversely correlated with transcription. While our study was controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.

Background Measuring the quantity of miRNAs in tissues of different physiological and pathological conditions is an important first step to investigate the functions of miRNAs. Matched samples from normal state can provide essential baseline references to analyze the variation of miRNA abundance. Results We provided expression data of 345 miRNAs in 40 normal human tissues, which identified universally expressed miRNAs, and several groups of miRNAs expressed exclusively or preferentially in certain tissue types. Many miRNAs with co-regulated expression patterns are located within the same genomic clusters, and candidate transcriptional factors that control the pattern of their expression may be identified by a comparative genomic strategy. Hierarchical clustering of normal tissues by their miRNA expression profiles basically followed the structure, anatomical locations, and physiological functions of the organs, suggesting that functions of a miRNA could be appreciated by linking to the biologies of the tissues in which it is uniquely expressed. Many predicted target genes of miRNAs that had specific reduced expression in brain and peripheral blood mononuclear cells are required for embryonic development of the nervous and hematopoietic systems based on database search. Conclusion We presented a global view of tissue distribution of miRNAs in relation to their chromosomal locations and genomic structures. We also described evidence from the cis-regulatory elements and the predicted target genes of miRNAs to support their tissue-specific functional roles to regulate the physiologies of the normal tissues in which they are expressed.