Entropy Measures Quantify Global Splicing Disorders in Cancer

Most mammalian genes are able to express several splice variants in a phenomenon known as alternative splicing. Serious alterations of alternative splicing occur in cancer tissues, leading to expression of multiple aberrant splice forms. Most studies of alternative splicing defects have focused on the identification of cancer-specific splice variants as potential therapeutic targets. Here, we examine instead the bulk of non-specific transcript isoforms and analyze their level of disorder using a measure of uncertainty called Shannon's entropy. We compare isoform expression entropy in normal and cancer tissues from the same anatomical site for different classes of transcript variations: alternative splicing, polyadenylation, and transcription initiation. Whereas alternative initiation and polyadenylation show no significant gain or loss of entropy between normal and cancer tissues, alternative splicing shows highly significant entropy gains for 13 of the 27 cancers studied. This entropy gain is characterized by a flattening in the expression profile of normal isoforms and is correlated to the level of estimated cellular proliferation in the cancer tissue. Interestingly, the genes that present the highest entropy gain are enriched in splicing factors. We provide here the first quantitative estimate of splicing disruption in cancer. The expression of normal splice variants is widely and significantly disrupted in at least half of the cancers studied. We postulate that such splicing disorders may develop in part from splicing alteration in key splice factors, which in turn significantly impact multiple target genes

Deregulated expression of hnRNP A/B proteins in human non-small cell lung cancer: parallel assessment of protein and mRNA levels in paired tumour/non-tumour tissues

<p>Abstract</p> <p>Background</p> <p>Heterogeneous nuclear ribonucleoproteins (hnRNPs) of the A/B type (hnRNP A1, A2/B1, A3) are highly related multifunctional proteins participating in alternative splicing by antagonising other splicing factors, notably ASF/SF2. The altered expression pattern of hnRNP A2/B1 and/or splicing variant B1 alone in human lung cancer and their potential to serve as molecular markers for early diagnosis remain issues of intense investigation. The main objective of the present study was to use paired tumour/non-tumour biopsies from patients with non-small cell lung cancer (NSCLC) to investigate the expression profiles of hnRNP A1, A2/B1 and A3 in conjunction with ASF/SF2.</p> <p>Methods</p> <p>We combined western blotting of tissue homogenates with immunohistochemical examination of fixed tissue sections and quantification of mRNA expression levels in tumour versus adjacent normal-looking areas of the lung in the same patient.</p> <p>Results</p> <p>Our study, in addition to clear evidence of mostly uncoupled deregulation of hnRNPs A/B, has revealed hnRNP A1 to be the most deregulated protein with a high frequency of over-expression (76%), followed by A3 (52%) and A2/B1 (43%). Moreover, direct comparison of protein/mRNA levels showed a lack of correlation in the case of hnRNP A1 (as well as of ASF/SF2), but not of A2/B1, suggesting that different mechanisms underlie their deregulation.</p> <p>Conclusion</p> <p>Our results provide strong evidence for the up-regulation of hnRNP A/B in NSCLC, and they support the existence of distinct mechanisms responsible for their deregulated expression.</p

Ectomycorrhizal fungal communities of native and non-native Pinus and Quercus species in a common garden of 35-year-old trees

Non-native tree species have been widely planted or have become naturalized in most forested landscapes. It is not clear if native trees species collectively differ in ectomycorrhizal fungal (EMF) diversity and communities from that of non-native tree species. Alternatively, EMF species community similarity may be more determined by host plant phylogeny than by whether the plant is native or non-native. We examined these unknowns by comparing two genera, native and non-native Quercus robur and Quercus rubra and native and non-native Pinus sylvestris and Pinus nigra in a 35-year-old common garden in Poland. Using molecular and morphological approaches, we identified EMF species from ectomycorrhizal root tips and sporocarps collected in the monoculture tree plots. A total of 69 EMF species were found, with 38 species collected only as sporocarps, 18 only as ectomycorrhizas, and 13 both as ectomycorrhizas and sporocarps. The EMF species observed were all native and commonly associated with a Holarctic range in distribution. We found that native Q. robur had ca. 120% higher total EMF species richness than the non-native Q. rubra, while native P. sylvestris had ca. 25% lower total EMF species richness than non-native P. nigra. Thus, across genera, there was no evidence that native species have higher EMF species diversity than exotic species. In addition, we found a higher similarity in EMF communities between the two Pinus species than between the two Quercus species. These results support the naturalization of non-native trees by means of mutualistic associations with cosmopolitan and novel fungi