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In silico prediction of housekeeping long intergenic non-coding RNAs reveals HKlincR1 as an essential player in lung cancer cell survival.

ABSTRACT: Prioritising long intergenic noncoding RNAs (lincRNAs) for functional characterisation is a significant challenge. Here we applied computational approaches to discover lincRNAs expected to play a critical housekeeping (HK) role within the cell. Using the Illumina Human BodyMap RNA sequencing dataset as a starting point, we first identified lincRNAs ubiquitously expressed across a panel of human tissues. This list was then further refined by reference to conservation score, secondary structure and promoter DNA methylation status. Finally, we used tumour expression and copy number data to identify lincRNAs rarely downregulated or deleted in multiple tumour types. The resulting list of candidate essential lincRNAs was then subjected to co-expression analyses using independent data from ENCODE and The Cancer Genome Atlas (TCGA). This identified a substantial subset with a predicted role in DNA replication and cell cycle regulation. One of these, HKlincR1, was selected for further characterisation. Depletion of HKlincR1 affected cell growth in multiple lung cancer cell lines, and led to disruption of genes involved in cell growth and viability. In addition, HKlincR1 expression was correlated with overall survival in lung adenocarcinoma patients. Our in silico studies therefore reveal a set of housekeeping noncoding RNAs of interest both in terms of their role in normal homeostasis, and their relevance in tumour growth and maintenance.

SUBMITTER: Memon D

PROVIDER: S-EPMC6517443 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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In silico prediction of housekeeping long intergenic non-coding RNAs reveals HKlincR1 as an essential player in lung cancer cell survival.

Memon Danish D Bi Jing J Miller Crispin J CJ

Scientific reports 20190514 1

Prioritising long intergenic noncoding RNAs (lincRNAs) for functional characterisation is a significant challenge. Here we applied computational approaches to discover lincRNAs expected to play a critical housekeeping (HK) role within the cell. Using the Illumina Human BodyMap RNA sequencing dataset as a starting point, we first identified lincRNAs ubiquitously expressed across a panel of human tissues. This list was then further refined by reference to conservation score, secondary structure an ...[more]

PMID: 31089191

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Project description:BackgroundLong intergenic non-coding RNAs (lincRNAs) can act as regulators of expression of protein-coding genes. Trans-natural antisense transcripts (trans-NATs) are a type of lincRNAs that contain sequence complementary to mRNA from other loci. The regulatory potential of trans-NATs has been poorly studied in eukaryotes and no example of trans-NATs regulating gene expression in plants are reported. The goal of this study was to identify lincRNAs, and particularly trans-NATs, in Arabidopsis thaliana that have a potential to regulate expression of target genes in trans at the transcriptional or translational level.ResultsWe identified 1001 lincRNAs using an RNAseq dataset from total polyA+ and polysome-associated RNA of seedlings grown under high and low phosphate, or shoots and roots treated with different phytohormones, of which 550 were differentially regulated. Approximately 30% of lincRNAs showed conservation amongst Brassicaceae and 25% harbored transposon element (TE) sequences. Gene co-expression network analysis highlighted a group of lincRNAs associated with the response of roots to low phosphate. A total of 129 trans-NATs were predicted, of which 88 were significantly differentially expressed under at least one pairwise comparison. Five trans-NATs showed a positive correlation between their expression and target mRNA steady-state levels, and three showed a negative correlation. Expression of four trans-NATs positively correlated with a change in target mRNA polysome association. The regulatory potential of these trans-NATs did not implicate miRNA mimics nor siRNAs. We also looked for lincRNAs that could regulate gene expression in trans by Watson-Crick DNA:RNA base pairing with target protein-encoding loci. We identified 100 and 81 with a positive or negative correlation, respectively, with steady-state level of their predicted target. The regulatory potential of one such candidate lincRNA harboring a SINE TE sequence was validated in a protoplast assay on three distinct genes containing homologous TE sequence in their promoters. Construction of networks highlighted other putative lincRNAs with multiple predicted target loci for which expression was positively correlated with target gene expression.ConclusionsThis study identified lincRNAs in Arabidopsis with potential in regulating target gene expression in trans by both RNA:RNA and RNA:DNA base pairing and highlights lincRNAs harboring TE sequences in such activity.

Project description:BACKGROUND:Long non-coding RNAs (lncRNAs) are key regulators of diverse cellular processes. Although a number of studies have reported the identification of bovine lncRNAs across many tissues, very little is known about the identity and characteristics of lncRNAs in bovine oocytes. METHODS:A bovine oocyte cDNA library was constructed and sequenced using the Illumina HiSeq 2000 sequencing system. The oocyte transcriptome was constructed using the ab initio assembly software Scripture and Cufflinks. The assembled transcripts were categorized to identify the novel intergenic transcripts, and the coding potential of these novel transcripts was assessed using CPAT and PhyloCSF. The resulting candidate long intergenic non-coding RNAs (lincRNAs) transcripts were further evaluated to determine if any of them contain any known protein coding domains in the Pfam database. RT-PCR was used to analyze the expression of oocyte-expressed lincRNAs in various bovine tissues. RESULTS:A total of 85 million raw reads were generated from sequencing of the bovine oocyte library. Transcriptome reconstruction resulted in the assembly of a total of 42,396 transcripts from 37,678 genomic loci. Analysis of the assembled transcripts using the step-wide pipeline resulted in the identification of 1535 oocyte lincRNAs corresponding to 1183 putative non-coding genes. A comparison of the oocyte lincRNAs with the lncRNAs reported in other bovine tissues indicated that 970 of the 1535 oocyte lincRNAs appear to be unique to bovine oocytes. RT-PCR analysis of 5 selected lincRNAs showed either specific or predominant expression of 4 lincRNAs in the fetal ovary. Functional prediction of the oocyte-expressed lincRNAs suggested their involvement in oogenesis through regulating their neighboring protein-coding genes. CONCLUSIONS:This study provides a starting point for future research aimed at understanding the roles of lncRNAs in controlling oocyte development and early embryogenesis in cattle.

Project description:Recently, large numbers of normal human tissues have been profiled for non-coding RNAs and more than fourteen thousand long intergenic non-coding RNAs (lincRNAs) are found expressed in normal human tissues. The functional roles of these normal lincRNAs (nlincRNAs) in the regulation of protein coding genes in normal and disease biology are yet to be established. Here, we have profiled two RNA-seq datasets including cancer and matched non-neoplastic tissues from 12 individuals from diverse demography for both coding genes and nlincRNAs. We find 130 nlincRNAs significantly regulated in cancer, with 127 regulated in the same direction in the two datasets. Interestingly, according to Illumina Body Map, significant numbers of these nlincRNAs display baseline null expression in normal prostate tissues but are specific to other tissues such as thyroid, kidney, liver and testis. A number of the regulated nlincRNAs share loci with coding genes, which are either co-regulated or oppositely regulated in all cancer samples studied here. For example, in all cancer samples i) the nlincRNA, TCONS_00029157, and a neighboring tumor suppressor factor, SIK1, are both down regulated; ii) several thyroid-specific nlincRNAs in the neighborhood of the thyroid-specific gene TPO, are both up-regulated; and iii) the TCONS_00010581, an isoform of HEIH, is down-regulated while the neighboring EZH2 gene is up-regulated in cancer. Several nlincRNAs from a prostate cancer associated chromosomal locus, 8q24, are up-regulated in cancer along with other known prostate cancer associated genes including PCAT-1, PVT1, and PCAT-92. We observe that there is significant bias towards up-regulation of nlincRNAs with as high as 118 out of 127 up-regulated in cancer, even though regulation of coding genes is skewed towards down-regulation. Considering that all reported cancer associated lincRNAs (clincRNAs) are biased towards up-regulation, we conclude that this bias may be functionally relevant.

Dataset Information

In silico prediction of housekeeping long intergenic non-coding RNAs reveals HKlincR1 as an essential player in lung cancer cell survival.

Publications

In silico prediction of housekeeping long intergenic non-coding RNAs reveals HKlincR1 as an essential player in lung cancer cell survival.

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