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Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder with typical neuropathological hallmarks, such as neuritic plaques and neurofibrillary tangles, preferentially found at layers III and V. The distribution of both hallmarks provides the basis for the staging of AD, following a hierarchical pattern throughout the cerebral cortex. To unravel the background of this layer-specific vulnerability, we evaluated differential gene expression of supragranular and infragranular layers and subcortical white matter in both healthy controls and AD patients. We identified AD-associated layer-specific differences involving protein-coding and non-coding sequences, most of those present in the subcortical white matter, thus indicating a critical role for long axons and oligodendrocytes in AD pathomechanism. In addition, GO analysis identified networks containing synaptic vesicle transport, vesicle exocytosis and regulation of neurotransmitter levels. Numerous AD-associated layer-specifically expressed genes were previously reported to undergo layer-specific switches in recent hominid brain evolution between layers V and III, i.e., those layers that are most vulnerable to AD pathology. Against the background of our previous finding of accelerated evolution of AD-specific gene expression, here we suggest a critical role in AD pathomechanism for this phylogenetic layer-specific adaptation of gene expression, which is most prominently seen in the white matter compartment.

BackgroundColorectal cancer (CRC) is a heterogeneous cancer. Its treatment depends on its anatomical site and distinguishes between colon, rectum, and rectosigmoid junction cancer. This study aimed to identify diagnostic and prognostic biomarkers using networks of CRC-associated transcripts that can be built based on competing endogenous RNAs (ceRNA).MethodsRNA expression and clinical information data of patients with colon, rectum, and rectosigmoid junction cancer were obtained from The Cancer Genome Atlas (TCGA). The RNA expression profiles were assessed through bioinformatics analysis, and a ceRNA was constructed for each CRC site. A functional enrichment analysis was performed to assess the functional roles of the ceRNA networks in the prognosis of colon, rectum, and rectosigmoid junction cancer. Finally, to verify the ceRNA impact on prognosis, an overall survival analysis was performed.ResultsThe study identified various CRC site-specific prognosis biomarkers: hsa-miR-1271-5p, NRG1, hsa-miR-130a-3p, SNHG16, and hsa-miR-495-3p in the colon; E2F8 in the rectum and DMD and hsa-miR-130b-3p in the rectosigmoid junction. We also identified different biological pathways that highlight differences in CRC behavior at different anatomical sites, thus reinforcing the importance of correctly identifying the tumor site.ConclusionsSeveral potential prognostic markers for colon, rectum, and rectosigmoid junction cancer were found. CeRNA networks could provide better understanding of the differences between, and common factors in, prognosis of colon, rectum, and rectosigmoid junction cancer.

Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are the most common histological types of cervical cancer (CC). The worse prognosis of ADC cases highlights the need for better molecular characterization regarding differences between these CC types. RNA-Seq analysis of seven SCC and three ADC human papillomavirus 16-positive samples and the comparison with public data from non-tumoral human papillomavirus-negative cervical tissue samples revealed pathways exclusive to each histological type, such as the epithelial maintenance in SCC and the maturity-onset diabetes of the young (MODY) pathway in ADC. The transcriptional regulatory network analysis of cervical SCC samples unveiled a set of six transcription factor (TF) genes with the potential to positively regulate long non-coding RNA genes DSG1-AS1, CALML3-AS1, IGFL2-AS1, and TINCR. Additional analysis revealed a set of MODY TFs regulated in the sequence predicted to be repressed by miR-96-5p or miR-28-3p in ADC. These microRNAs were previously described to target LINC02381, which was predicted to be positively regulated by two MODY TFs upregulated in cervical ADC. Therefore, we hypothesize LINC02381 might act by decreasing the levels of miR-96-5p and miR-28-3p, promoting the MODY activation in cervical ADC. The novel TF networks here described should be explored for the development of more efficient diagnostic tools.

Abstract Spliced leader dependent trans-splicing (SLTS) has been described as an important RNA regulatory process that occurs in different organisms, including the trematode Schistosoma mansoni. We identified more than seven thousand putative SLTS sites in the parasite, comprising genes with a wide spectrum of functional classes, which underlines the SLTS as a ubiquitous mechanism in the parasite. Also, SLTS gene expression levels span several orders of magnitude, showing that SLTS frequency is not determined by the expression level of the target gene, but by the presence of particular gene features facilitating or hindering the trans-splicing mechanism. Our in-depth investigation of SLTS events demonstrates widespread alternative trans-splicing (ATS) acceptor sites occurring in different regions along the entire gene body, highlighting another important role of SLTS generating alternative RNA isoforms in the parasite, besides the polycistron resolution. Particularly for introns where SLTS directly competes for the same acceptor substrate with cis-splicing, we identified for the first time additional and important features that might determine the type of splicing. Our study substantially extends the current knowledge of RNA processing by SLTS in S. mansoni, and provide basis for future studies on the trans-splicing mechanism in other eukaryotes.

Lung cancer is one of the most frequent types of cancer worldwide. Most patients are diagnosed at advanced stage and thus have poor prognosis. Smoking is a risk factor for lung cancer, however most smokers do not develop lung cancer while 20% of women with lung adenocarcinoma are non-smokers. Therefore, it is possible that these two groups present differences besides the smoking status, including differences in their gene expression signature. The altered expression patterns of non-coding RNAs in complex diseases make them potential biomarkers for diagnosis and treatment. We analyzed data from differentially and constitutively expressed PIWI-interacting RNAs and small nucleolar RNAs from publicly available small RNA high-throughput sequencing data in search of an expression pattern of non-coding RNA that could differentiate these two groups. Here, we report two sets of differentially expressed small non-coding RNAs identified in normal and tumoral tissues of women with lung adenocarcinoma, that discriminate between smokers and non-smokers. Our findings may offer new insights on metabolic alterations caused by tobacco and may be used for early diagnosis of lung cancer.

The numerous genome sequencing projects produced unprecedented amount of data providing significant information to the discovery of novel noncoding RNA (ncRNA). Several ncRNAs have been described to control gene expression and display important role during cell differentiation and homeostasis. In the last decade, high throughput methods in conjunction with approaches in bioinformatics have been used to identify, classify and evaluate the expression of hundreds of ncRNA in normal and pathological states, such as cancer. Patient outcomes have been already associated with differential expression of ncRNAs in normal and tumoral tissues, providing new insights in the development of innovative therapeutic strategies in oncology. In this review, we present and discuss bioinformatics advances in the development of computational approaches to analyze and discover ncRNA data in oncology using high throughput sequencing technologies.