Discovery pipeline for epigenetically deregulated miRNAs in cancer: integration of primary miRNA transcription

<p>Abstract</p> <p>Background</p> <p>Cancer is commonly associated with widespread disruption of DNA methylation, chromatin modification and miRNA expression. In this study, we established a robust discovery pipeline to identify epigenetically deregulated miRNAs in cancer.</p> <p>Results</p> <p>Using an integrative approach that combines primary transcription, genome-wide DNA methylation and H3K9Ac marks with microRNA (miRNA) expression, we identified miRNA genes that were epigenetically modified in cancer. We find miR-205, miR-21, and miR-196b to be epigenetically repressed, and miR-615 epigenetically activated in prostate cancer cells.</p> <p>Conclusions</p> <p>We show that detecting changes in primary miRNA transcription levels is a valuable method for detection of local epigenetic modifications that are associated with changes in mature miRNA expression.</p

MicroRNA Alterations and Associated Aberrant DNA Methylation Patterns across Multiple Sample Types in Oral Squamous Cell Carcinoma

Background: MicroRNA (miRNA) expression is broadly altered in cancer, but few studies have investigated miRNA deregulation in oral squamous cell carcinoma (OSCC). Epigenetic mechanisms are involved in the regulation of .30 miRNA genes in a range of tissues, and we aimed to investigate this further in OSCC. Methods: TaqManH qRT-PCR arrays and individual assays were used to profile miRNA expression in a panel of 25 tumors with matched adjacent tissues from patients with OSCC, and 8 control paired oral stroma and epithelium from healthy volunteers. Associated DNA methylation changes of candidate epigenetically deregulated miRNA genes were measured in the same samples using the MassArrayH mass spectrometry platform. MiRNA expression and DNA methylation changes were also investigated in FACS sorted CD44high oral cancer stem cells from primary tumor samples (CSCs), and in oral rinse and saliva from 15 OSCC patients and 7 healthy volunteers. Results: MiRNA expression patterns were consistent in healthy oral epithelium and stroma, but broadly altered in both tumor and adjacent tissue from OSCC patients. MiR-375 is repressed and miR-127 activated in OSCC, and we confirm previous reports of miR-137 hypermethylation in oral cancer. The miR-200 s/miR-205 were epigenetically activated in tumors vs normal tissues, but repressed in the absence of DNA hypermethylation specifically in CD44high oral CSCs. Aberrant miR-375 and miR-200a expression and miR-200c-141 methylation could be detected in and distinguish OSCC patient oral rinse and saliva from healthy volunteers, suggesting a potential clinical application for OSCC specific miRNA signatures in oral fluids. Conclusions: MiRNA expression and DNA methylation changes are a common event in OSCC, and we suggest miR-375, miR- 127, miR-137, the miR-200 family and miR-205 as promising candidates for future investigations. Although overall activated in OSCC, miR-200/miR-205 suppression in oral CSCs indicate that cell specific silencing of these miRNAs may drive tumor expansion and progression

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses

BACKGROUND Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11–q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate 70: 735–744, 2010. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71371/1/21106_ftp.pd

The Long Term Response of Birds to Climate Change: New Results from a Cold Stage Avifauna in Northern England

The early MIS 3 (55–40 Kyr BP associated with Middle Palaeolithic archaeology) bird remains from Pin Hole, Creswell Crags, Derbyshire, England are analysed in the context of the new dating of the site’s stratigraphy. The analysis is restricted to the material from the early MIS 3 level of the cave because the upper fauna is now known to include Holocene material as well as that from the Late Glacial. The results of the analysis confirm the presence of the taxa, possibly unexpected for a Late Pleistocene glacial deposit including records such as Alpine swift, demoiselle crane and long-legged buzzard with southern and/or eastern distributions today. These taxa are accompanied by more expected ones such as willow ptarmigan /red grouse and rock ptarmigan living today in northern and montane areas. Finally, there are temperate taxa normally requiring trees for nesting such as wood pigeon and grey heron. Therefore, the result of the analysis is that the avifauna of early MIS 3 in England included taxa whose ranges today do not overlap making it a non-analogue community similar to the many steppe-tundra mammalian faunas of the time. The inclusion of more temperate and woodland taxa is discussed in the light that parts of northern Europe may have acted as cryptic northern refugia for some such taxa during the last glacial. These records showing former ranges of taxa are considered in the light of modern phylogeographic studies as these often assume former ranges without considering the fossil record of those taxa. In addition to the anomalous combination of taxa during MIS 3 living in Derbyshire, the individuals of a number of the taxa are different in size and shape to members of the species today probably due to the high carrying capacity of the steppe-tundra