Browsing by Author "Karakulah, Gokhan"

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Citation - WoS: 36
Citation - Scopus: 39
Alteration of Mirnas in Small Neuron-Derived Extracellular Vesicles of Alzheimer's Disease Patients and the Effect of Extracellular Vesicles on Microglial Immune Responses
(Springernature, 2022) Durur, Devrim Yagmur; Tastan, Bora; Tufekci, Kemal Ugur; Olcum, Melis; Uzuner, Hamdiye; Karakulah, Gokhan; Yener, Görsev; Ugur Tufekci, Kemal; Genc, Sermin
Alzheimer's disease (AD) is one of the most severe neurodegenerative diseases observed in the elderly population. Although the hallmarks of AD have been identified, the methods for its definitive diagnosis and treatment are still lacking. Extracellular vesicles (EVs) have become a promising source for biomarkers since the identification of their content. EVs are released from multiple cell types and, when released from neurons, they pass from the brain to the blood with their cargo molecules. Hence, neuron-specific EV-resident microRNAs (miRNAs) are promising biomarkers for diagnosis of AD. This study aimed to identify altered miRNA content in small neuron-derived extracellular vesicles (sNDEVs) isolated from AD patients and healthy individuals. Furthermore, we examined the role of sNDEV-resident miRNAs in neuron-glia cellular interaction to understand their role in AD propagation. We identified 10 differentially expressed miRNAs in the sNDEVs of patients via next-generation sequencing and validated the most dysregulated miRNA, let-7e, with qRT-PCR. Let-7e was significantly increased in the sNDEVs of AD patients compared with those of healthy controls in a larger cohort. First, we evaluated the diagnostic utility of let-7e via ROC curve analysis, which revealed an AUC value of 0.9214. We found that IL-6 gene expression was increased in human microglia after treatment with sNDEVs of AD patients with a high amount of let-7e. Our study suggests that sNDEV-resident let-7e is a potential biomarker for AD diagnosis, and that AD patient-derived sNDEVs induce a neuroinflammatory response in microglia.
Citation - WoS: 17
Citation - Scopus: 18
Dysregulated Expression of Repetitive Dna in Er+/Her2-breast Cancer
(Elsevier Science Inc, 2019) Yandim, Cihangir; Karakulah, Gokhan
Limited 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.
Citation - WoS: 41
Citation - Scopus: 41
Expression Dynamics of Repetitive Dna in Early Human Embryonic Development
(Bmc, 2019) Yandim, Cihangir; Karakulah, Gokhan
Background: 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. Results: We uncovered stage-specific expressions of more than a thousand repeat elements whose expressions fluctuated with a mild global decrease at the blastocyst stage. Most satellites were highly expressed at the 4-cell level and expressions of ACRO1 and D20S16 specifically peaked at this point. Whereas all members of the SVA elements were highly upregulated at 8-cell and morula stages, other transposons and small RNA repeats exhibited a high level of variation among their specific subtypes. Our repeat enrichment analysis in gene promoters coupled with expression correlations highlighted potential links between repeat expressions and nearby genes, emphasising mostly 8-cell and morula specific genes together with SVA_D, LTR5_Hs and LTR70 transposons. The DNA methylation analysis further complemented the understanding on the mechanistic aspects of the repeatome's regulation per se and revealed critical stages where DNA methylation levels are negatively correlating with repeat expression. Conclusions: Taken together, our study shows that specific expression patterns are not exclusive to genes and longnon-coding RNAs but the repeatome also exhibits an intriguingly dynamic pattern at the global scale. Repeats identified in this study; particularly satellites, which were historically associated with heterochromatin, and those with potential links to nearby gene expression provide valuable insights into the understanding of key events in genomic regulation and warrant further research in epigenetics, genomics and developmental biology.
Citation - WoS: 4
Citation - Scopus: 5
Identification of Differentially Expressed Genomic Repeats in Primary Hepatocellular Carcinoma and Their Potential Links To Biological Processes and Survival
(Scientific And Technological Research Council Turkey, 2021) Karakulah, Gokhan; Yandim, Cihangir
Hepatocellular 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.
Citation - WoS: 2
Citation - Scopus: 3
Repeat Expression Is Linked To Patient Survival and Exhibits Single Nucleotide Variation in Pancreatic Cancer Revealing Ltr70:r.879a > G
(Elsevier, 2022) Yandim, Cihangir; Karakulah, Gokhan
Despite 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.
Citation - WoS: 7
Citation - Scopus: 8
Signature Changes in the Expressions of Protein-Coding Genes, Lncrnas, and Repeat Elements in Early and Late Cellular Senescence
(Tubitak Scientific & Technical Research Council Turkey, 2020) Karakulah, Gokhan; Yandim, Cihangir
Replicative 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.
Citation - WoS: 21
Citation - Scopus: 20
Teffectr: an R Package for Studying the Potential Effects of Transposable Elements on Gene Expression With Linear Regression Model
(Peerj Inc, 2019) Karakulah, Gokhan; Arslan, Nazmiye; Yandim, Cihangir; Suner, Asli
Introduction. 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.