Dysregulation of Transcription Factor Networks Unveils Different Pathways in Human Papillomavirus 16-Positive Squamous Cell Carcinoma and Adenocarcinoma of the Uterine Cervix

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 bymiR-96-5p ormiR-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 LINC02381might act by decreasing the levels ofmiR-96-5p andmiR-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

Competing Endogenous RNA in Colorectal Cancer: An Analysis for Colon, Rectum, and Rectosigmoid Junction

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

Utilização de RNAs não codificadores pequenos na distinção de amostras humanas de câncer de pulmão e de células do sangue

Made available in DSpace on 2018-03-07T16:57:48Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) natasha_jorge_ioc_dout_2017.pdf: 8835307 bytes, checksum: 6a4f2cef2e7caa403a2bc10670773108 (MD5)Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Os RNAs não codificadores pequenos, como piRNAs, snoRNAs e miRNAs, atuam em diversas etapas do metabolismo celular, participando de processos como controle da expressão gênica, metilação e pseudouridilação de rRNAs e diferenciação celular. Neste trabalho, utilizamos dados públicos de sequenciamento de alta vazão de RNAs pequenos para avaliar a importância de RNAs não codificadores pequenos na biologia das células sadias e de neoplasia maligna. Na primeira análise, utilizamos dados de amostras normais e tumorais de pacientes de adenocarcinoma de pulmão obtidos no banco de dados do TCGA. Estas amostras foram utilizadas para avaliar o perfil de expressão de snoRNAs e piRNAs. Nesta análise, revelamos que o fumo inibe diversos snoRNAs relacionados à manutenção celular e promove a expressão de outros snoRNAs também encontrados mais expressos em diversos tumores, alterando, assim, o perfil de expressão de células normais para um que se assemelha mais a tumores. Também monstramos que os tumores de pulmão de não fumantes e fumantes são bastante heterogêneos e aconselhamos que sejam estudados separadamente Nesta mesma análise, apontamos também snoRNAs cuja expressão não se altera em nenhuma das condições avaliadas, podendo assim serem usados como parâmetro para normalização de experimentos de biologia molecular. A segunda análise envolve a identificação de miRNAs diferencialmente expressos entre linfócitos T CD4 virgens, megacariócitos, eritroblatos, neutrófilos, monócitos e macrófagos M1 e M2 do projeto Blueprint. Nesta etapa, além de identificar os miRNAs, utilizamos dados de sequenciamento de alta vazão de mRNAs e um banco de dados de alvos validados para identificar as vias metabólicas inibidas por miRNAs durante o processo de diferenciação destes tipos celulares. Esta análise corrobora dados da literatura do papel de miRNAs no processo de diferenciação e ativação de diversas células da linhagem hematopoética. Em conjunto, as duas análises reforçam o papel dos RNAs não codificadores na manutenção do metabolismo celularThe small non-coding RNAs, such as piRNAs, snoRNAs and miRNAs act at several stages of cellular metabolism, participating in processes such as gene expression control, molecule modification and cell differentiation. In this work, we used public high-throughput sequencing data of small RNAs to evaluate the importance of small non-coding RNAs in in healthy cell and malignant neoplasm biology. In the first analysis, we used data from normal and tumor samples from lung adenocarcinoma patients obtained from the TCGA database. These samples were used to evaluate the expression profile of snoRNAs and piRNAs. In this analysis, we have shown that smoking inhibits several snoRNAs related to cell maintenance and promotes the expression of other snoRNAs also found to be more expressed in several tumors, thereby altering the expression profile of normal cells towards one that resembles more tumors cells. We have also demonstrated that lung tumors of nonsmokers and smokers are quite heterogeneous and should be studied separately. In this same analysis, we also point out snoRNAs whose expression does not change in any of the cellular types evaluated, and can thus be used as a parameter for quantification in molecular biology experiments The second analysis involves the identification of differentially expressed miRNAs between lymphocytes T CD4 naive, megakaryocytes, erythrocytes, neutrophils, monocytes, and macrophages M1 and M2 from the Blueprint project. In this step, in addition to identifying altered miRNAs, we used high-throughput sequencing data from mRNAs and a database of validated targets to identify metabolic pathways inhibited by miRNAs during the differentiation process of these cell types. This analysis corroborates data from the literature on the role of miRNAs in the process of differentiation and activation of several cells of the hematopoietic lineage. Together, the two analyzes reinforce the role of non-coding RNAs in the maintenance of cellular metabolis

Bioinformatics of cancer ncRNA in high throughput sequencing: present state and challenges

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

Unraveling RNA dynamical behavior of TPP riboswitches: a comparison between Escherichia coli and Arabidopsis thaliana

Submitted by Manoel Barata ([email protected]) on 2019-04-30T15:50:52Z No. of bitstreams: 1 41598_2019_Article_40875.pdf: 8041209 bytes, checksum: a824ccf0635d7165f090a5ce2df9c212 (MD5)Approved for entry into archive by Manoel Barata ([email protected]) on 2019-05-20T15:06:54Z (GMT) No. of bitstreams: 1 41598_2019_Article_40875.pdf: 8041209 bytes, checksum: a824ccf0635d7165f090a5ce2df9c212 (MD5)Made available in DSpace on 2019-05-20T15:06:54Z (GMT). No. of bitstreams: 1 41598_2019_Article_40875.pdf: 8041209 bytes, checksum: a824ccf0635d7165f090a5ce2df9c212 (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Presidência. Programa de Computação Científica. Grupo de Biofísica Computacional e Modelagem Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Presidência. Programa de Computação Científica. Grupo de Biofísica Computacional e Modelagem Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Regulação da Expressão Gênica. Curitiba, PR, Brasil.Fundação Oswaldo Cruz. Presidência. Programa de Computação Científica. Grupo de Biofísica Computacional e Modelagem Molecular. Rio de Janeiro, RJ, Brasil.Riboswitches are RNA sensors that affect post-transcriptional processes through their ability to bind to small molecules. Thiamine pyrophosphate (TPP) riboswitch class is the most widespread riboswitch occurring in all three domains of life. Even though it controls different genes involved in the synthesis or transport of thiamine and its phosphorylated derivatives in bacteria, archaea, fungi, and plants, the TPP aptamer has a conserved structure. In this study, we aimed at understanding differences in the structural dynamics of TPP riboswitches from Escherichia coli and Arabidopsis thaliana, based on their crystallographic structures (TPPswec and TPPswat, respectively) and dynamics in aqueous solution, both in apo and holo states. A combination of Molecular Dynamics Simulations and Network Analysis empowered to find out slight differences in the dynamical behavior of TPP riboswitches, although relevant for their dynamics in bacteria and plants species. Our results suggest that distinct interactions in the microenvironment surrounding nucleotide U36 of TPPswec (and U35 in TPPswat) are related to different responses to TPP. The network analysis showed that minor structural differences in the aptamer enable enhanced intramolecular communication in the presence of TPP in TPPswec, but not in TPPswat. TPP riboswitches of plants present subtler and slower regulation mechanisms than bacteria do

snoRNA and piRNA expression levels modified by tobacco use in women with lung adenocarcinoma

<div><p>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.</p></div

Top 10 differentially expressed snoRNA between tumor samples from smokers and non-smokers.

<p>Top 10 differentially expressed snoRNA between tumor samples from smokers and non-smokers.</p

Top 10 differentially expressed snoRNAs between normal tissue samples from non-smokers and smokers.

<p>Top 10 differentially expressed snoRNAs between normal tissue samples from non-smokers and smokers.</p

Top 10 constitutively expressed snoRNA in samples from non-smokers.

<p>Top 10 constitutively expressed snoRNA in samples from non-smokers.</p

Scatterplot of the log2 fold change for the 28 snoRNAs shared between analysis.

<p>Scatterplot of the log2 fold change for the 28 snoRNAs shared between analysis.</p