Browsing by Subject "lncRNA"
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Item Open Access Discovering regulatory non-coding RNA interactions(2019-09) Olgun, GüldenThe vast majority of eukaryotic transcriptomes comprise noncoding RNAs (ncRNAs) which are not translated into proteins. Despite the accumulating evidence on the functional roles of ncRNAs, we are still far from understanding the whole spectrum of molecular functions ncRNAs can undertake and how they accomplish them. In this thesis we develop computational methods for discovering interactions among ncRNAs and tools to analyze them functionally. In the first part of the thesis, we present an integrative approach to discover long non-coding RNA (lncRNA) mediated sponge interactions where lncRNAs can indirectly regulate mRNAs expression levels by sequestering microRNAs (miRNAs), and act as sponges. We conduct partial correlation analysis and kernel independence tests on patient gene expression profiles and further refine the candidate interactions with miRNA target information. We use this approach to find sponge interactions specific to breast-cancer subtypes. We find that although there are sponges common to multiple subtypes, there are also distinct subtype-specific interactions with high prognostic potential. Secondly, we develop a method to identify synergistically acting miRNA pairs. These pairs have weak or no repression on the target mRNA when they act individually, but when together they induce strong repression of their target gene expression. We test the combinations of RNA triplets using non-parametric kernel-based interaction tests. In forming the triplets to test, we consider target predictions between the miRNAs and mRNA. We apply our approach on kidney tumor samples. The discovered triplets have several lines of biological evidence on a functional association among them or their relevance to kidney tumors. In the third part of the thesis, we focus on functional enrichment analysis of noncoding RNAs while some non-coding RNAs (ncRNAs) have been found to play critical regulatory roles in biological processes, most remain functionally uncharacterized. This presents a challenge whenever an interesting set of ncRNAs set needs to be analyzed in a functional context. We develop a method that performs cis enrichment analysis for a given set of ncRNAs. Enrichment is carried out by using the functional annotations of the coding genes located proximally to the input ncRNAs. To demonstrate how this method could be used to gain insight into the functional importance of a list of interesting ncRNAs, we tackle different biological questions on datasets of cancer and psychiatric disorders. Particularly, we also analyze 28 different types of cancers in terms of molecular process perturbed and linked to altered lncRNA expression. We hope that the methods developed herein will help elucidate functional roles of ncRNAs and aid the development of therapies based on ncRNAs.Item Open Access Identification of long non-coding RNAs overcoming tamoxifen resistance in estrogen receptor alpha positive breast cancer(2017-09) Bal, HilalMost of the breast cancer incidences all over the world fall into Estrogen Receptor alpha (ERα)-positive breast cancer subtype, which are treated with endocrine therapy. Tamoxifen, a selective ER modulator drug, is the most prescribed endocrine therapy option for the patients, providing a decreased mortality rate. Although patients respond to tamoxifen well initially they may lose their sensitivity to tamoxifen and develop resistance which is a major obstacle when tackling ERα-positive breast cancer. Global transcriptome analyses performed in recent years demonstrated that most parts of the genomic DNA that are transcribed into RNA are not further translated into proteins. RNA molecules that are not converted into proteins and are therefore called non-coding RNAs (ncRNA) were found to be involved in cellular processes like sequence-specific chromosome modifications, gene silencing and regulation of protein signaling pathways. While the roles of protein and microRNA (miRNA) regulators in the tamoxifen resistance have been identified, the roles of long non-coding RNAs in tamoxifen resistance are still elusive. To elucidate the impact of the long non-coding transcripts in tamoxifen resistance, I have developed acquired tamoxifen resistant ERα-positive cell line models and examined alterations in their transcriptome with respect to long non-coding RNA expression. The results of whole genome RNA-Seq analysis showed that 330 long non-coding transcripts were differentially expressed in the tamoxifen resistant cell line compared to its parental counterpart. I filtered-out ncRNAs according to criteria based on fold change, cancer association, and being a validated lncRNA, and I ended up with two candidate lncRNAs. Here, I continued with the upregulated candidate lncRNA and confirmed its elevated expression by qRT-PCR in both of the in vitro acquired tamoxifen resistant cell line models I used. Moreover, I showed that knockdown of the candidate lncRNA using antisense oligonucleotide (ASO) re-sensitizes resistant cells to tamoxifen. This sensitization effect of candidate lncRNA was achieved via induction of autophagy shown by increased LC3 II/LC3 I ratio followed by apoptosis evidenced by cleaved Caspase 7 when the lncRNA was targeted. Finally, analysis of tamoxifen-treated, ERα-positive breast cancer patient data sets suggested that higher expression of the candidate lncRNA was associated with poor overall, relapse-free and disease-free survival of the patients. Overall, in this thesis, I identified a novel lncRNA regulator of tamoxifen resistance and a potential biomarker of therapy response.Item Open Access Non-coding RNAs as emerging players in the development, diagnosis, and treatment of cancer(Frontiers Research Foundation, 2024-07-23) Golla, Upendarrao; Chachoua, Ilyas