1,720,966 research outputs found
TEffectR: an R package for studying the potential effects of transposable elements on gene expression with linear regression model
No full textYANDIM, Cihangir/0000-0002-2050-6186Introduction. Recent studies highlight the crucial regulatory roles of transposable elements (TEs) on proximal gene expression in distinct biological contexts such as disease and development. However, computational tools extracting potential TE - proximal gene expression associations from RNA-sequencing data are still missing. Implementation. Herein, we developed a novel R package, using a linear regression model, for studying the potential influence of TE species on proximal gene expression from a given RNA-sequencing data set. Our R package, namely TEffectR, makes use of publicly available RepeatMasker TE and Ensembl gene annotations as well as several functions of other R-packages. It calculates total read counts of TEs from sorted and indexed genome aligned BAM files provided by the user, and determines statistically significant relations between TE expression and the transcription of nearby genes under diverse biological conditions
Heterochromatin effects in Friedreich's ataxia and sexual dimorphism
Get PDFHeterochromatin is implicated in the negative regulation of gene expression. To understand the effects of heterochromatin on RNA polymerase-II (RNAPII) mediated transcription, this study focused on the FXN gene where abnormal silencing induced by expanded (GAA)n repeats causes Friedreich's ataxia (FRDA), an incurable neurological disorder. Here, the silenced FXN locus was found to be modified by the heterochromatic histone marks H3K9me3, H3K27me3 and bound by HP1β. This pathological heterochromatinisation was partially reversed by the histone deacetlyase inhibitor nicotinamide, which upregulated FXN expression to potentially therapeutic levels in vitro, ex vivo and in vivo. In addition, RNAPII was shown to be stalled in the first exon of the FXN gene and degraded by the proteasome in FRDA but not in healthy cells. This was linked to increased proteasome binding at the -silenced FXN locus in a pattern reminiscent of the heterochromatin marks. Importantly, proteasome inhibition restored stalled RNAPII levels in FRDA and upregulated FXN to potentially therapeutic levels in vitro. Moreover, experiments with healthy human cells and wild-type mouse thymus revealed enriched levels of proteasome binding in other heterochromatic regions (e.g. pericentromeric repeats and SINEs) which were also de-repressed by proteasome inhibition; suggesting that the effect seen on the pathological FXN locus represented a specific example of a more generalised phenomenon. Overall, this introduces a novel mechanism whereby heterochromatin might be maintained in a silent state.
In this thesis, heterochromatin effects were also investigated in relation to sexually dimorphic gene expression. Microarray analyses revealed hundreds of autosomal genes sensitive to sex chromosome-complement rather than gender. HP1β-repressed genes and SINE elements were over-represented within this gene group suggesting a potential link between heterochromatin, proteasome-dependent silencing and sexually dimorphic gene expression. The results reveal a novel layer in the regulation of sexually dimorphic genes with implications for understanding sex-bias in physiology and disease
Identification of differentially expressed genomic repeats in primary hepatocellular carcinoma and their potential links to biological processes and survival
No full textHepatocellular carcinoma (HCC) is one of the deadliest cancers. Research on HCC so far primarily focused on genes and provided limited information on genomic repeats, which constitute more than half of the human genome and contribute to genomic stability. In line with this, repeat dysregulation was significantly shown to be pathological in various cancers and other diseases. In this study, we aimed to determine the full repeat expression profile of HCC for the first time. We utilised two independent RNA-seq datasets obtained from primary HCC tumours with matched normal tissues of 20 and 17 HCC patients, respectively. We quantified repeat expressions and analysed their differential expression. We also identified repeats that are cooperatively expressed with genes by constructing a gene coexpression network. Our results indicated that HCC tumours in both datasets harbour 24 differentially expressed repeats and even more elements were coexpressed with genes involved in various metabolic pathways. We discovered that two L1 elements (L1M3b, L1M3de) were downregulated and a handful of HERV subfamily repeats (HERV-Fc1-int, HERV3-int, HERVE_a-int, HERVK11D-int, HERVK14C-int, HERVL18-int) were upregulated with the exception of HERV1_LTRc, which was downregulated. Various LTR elements (LTR32, LTR9, LTR4, LTR52-int, LTR70) and MER elements (MER11C, MER11D, MER57C1, MER9a1, MER74C) were implicated along with few other subtypes including Charlie12, MLT2A2, Tigger15a, Tigger 17b. The only satellite repeat differentially expressed in both datasets was GSATII, whose expression was upregulated in 33 (>90%) out of 37 patients. Notably, GSATII expression correlated with HCC survival genes. Elements discovered here promise future studies to be considered for biomarker and HCC therapy research. The coexpression patterns GSATII satellite with HCC survival genes and the fact that it has been upregulated in the vast majority of patients make this repeat particularly stand out for HCC
Heterochromatin effects in Friedreich's ataxia and sexual dimorphism
No full textHeterochromatin is implicated in the negative regulation of gene expression. To understand the effects of heterochromatin on RNA polymerase-II (RNAPII) mediated transcription, this study focused on the FXN gene where abnormal silencing induced by expanded (GAA)n repeats causes Friedreich's ataxia (FRDA), an incurable neurological disorder. Here, the silenced FXN locus was found to be modified by the heterochromatic histone marks H3K9me3, H3K27me3 and bound by HP1β. This pathological heterochromatinisation was partially reversed by the histone deacetlyase inhibitor nicotinamide, which upregulated FXN expression to potentially therapeutic levels in vitro, ex vivo and in vivo. In addition, RNAPII was shown to be stalled in the first exon of the FXN gene and degraded by the proteasome in FRDA but not in healthy cells. This was linked to increased proteasome binding at the -silenced FXN locus in a pattern reminiscent of the heterochromatin marks. Importantly, proteasome inhibition restored stalled RNAPII levels in FRDA and upregulated FXN to potentially therapeutic levels in vitro. Moreover, experiments with healthy human cells and wild-type mouse thymus revealed enriched levels of proteasome binding in other heterochromatic regions (e.g. pericentromeric repeats and SINEs) which were also de-repressed by proteasome inhibition; suggesting that the effect seen on the pathological FXN locus represented a specific example of a more generalised phenomenon. Overall, this introduces a novel mechanism whereby heterochromatin might be maintained in a silent state. In this thesis, heterochromatin effects were also investigated in relation to sexually dimorphic gene expression. Microarray analyses revealed hundreds of autosomal genes sensitive to sex chromosome-complement rather than gender. HP1β-repressed genes and SINE elements were over-represented within this gene group suggesting a potential link between heterochromatin, proteasome-dependent silencing and sexually dimorphic gene expression. The results reveal a novel layer in the regulation of sexually dimorphic genes with implications for understanding sex-bias in physiology and disease.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Signature changes in the expressions of protein-coding genes, lncRNAs, and repeat elements in early and late cellular senescence
No full textReplicative cellular senescence is the main cause of aging. It is important to note that early senescence is linked to tissue regeneration, whereas late senescence is known to trigger a chronically inflammatory phenotype. Despite the presence of various genome-wide studies, there is a lack of information on distinguishing early and late senescent phenotypes at the transcriptome level. Particularly, the changes in the noncoding RNA portion of the aging cell have not been fully elucidated. By utilising RNA sequencing data of fibroblasts, hereby, we are not only reporting changes in gene expression profiles and relevant biological processes in the early and late senescent phenotypes but also presenting significant differences in the expressions of many unravelled long noncoding RNAs (lncRNAs) and transcripts arisen from repetitive DNA. Our results indicate that, in addition to previously reported L1 elements, various LTR and DNA transposons, as well as members of the classical satellites including HSAT5 and alpha-satellites (ALR/Alpha), are expressed at higher levels in late senescence. Moreover, we revealed finer links between the expression levels of repeats with the genes located near them and known to be involved in cell cycle and senescence. Noncoding elements reported here provide a new perspective to be explored in further experimental studies
Expression dynamics of repetitive DNA in early human embryonic development
No full textBackground: The last decade witnessed a number of genome-wide studies on human pre-implantation, which mostly focused on genes and provided only limited information on repeats, excluding the satellites. Considering the fact that repeats constitute a large portion of our genome with reported links to human physiology and disease, a thorough understanding of their spatiotemporal regulation during human embryogenesis will give invaluable clues on chromatin dynamics across time and space. Therefore, we performed a detailed expression analysis of all repetitive DNA elements including the satellites across stages of human pre-implantation and embryonic stem cells
Dysregulated expression of repetitive DNA in ER+/HER2-breast cancer
No full textLimited studies on breast cancer indicated pathogenic changes in the expressions of some repeat elements. A global analysis was much needed within this context to distinguish the most significant repeats from more than a thousand repeat motifs. Utilising a previously presented RNA-seq dataset, we studied expression changes of all repeats in ER+/HER2- human breast tumour samples obtained from 22 patients in comparison to matched normal tissues. Fifty six (56) repeat subtypes including satellites and transposons were found to be differentially expressed and most of them were novel for breast cancer. HERVKC4-int and HERV1_LTRc, whose expressions correlated well with that of the estrogen receptor gene ESR1, were upregulated at the highest level. REP522 and D20S16 satellites were also significantly upregulated along with insignificant increases in the expressions of other satellites including HSATI and BSR/beta. Interestingly, expressions of REP522 and D20S16 correlated with many key breast cancer pathway (e.g. BRCA1, BRCA2, AKT1, MTOR, KRAS) and survival genes; possibly highlighting their importance in the carcinogenesis of breast. Additional differentially expressed elements such as L1P and various MER transposons also exhibited a similar pattern. Finally, our repeat enrichment analysis on the promoters of differentially expressed genes revealed further links between additional repeats and nearby genes. (C) 2019 Elsevier Inc. All rights reserved
Repeat expression is linked to patient survival and exhibits single nucleotide variation in pancreatic cancer revealing LTR70:r.879A>G
No full textDespite an overwhelming number of cancer literature reporting the links between patient survival and the expression levels of genes or mutations/single nucleotide variations (SNVs) on them, there is only limited information on repeat elements, which make at least half the human genome. Here, we analysed RNA-seq data obtained from primary pancreatic cancer tissues of 51 patients and revealed that two transposons, HERVI-int and X6A_LINE, showed an upregulation trend in the patients who lived shorter, along with 56 other potential repeats which were linked to survival. We also detected expressed single nucleotide variations (SNVs) on repeats, among which LTR70:r.879A>G stands out with the effect of its presence on this particular repeat's expression levels and a significant link to overall patient survival. Interestingly, the expression of LTR70:r.879A>G correlated with different cancer genes in comparison to its reference version highlighting the involvement of BRAF and Fumerate Hydratase with this expressed SNV. This is one of the first studies revealing possible links between repeat expression and survival in cancer and it warrants further research in this avenue
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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