Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Conference Object A Carbohydrate sulfotransferase mutant zebrafish shows importance of keratan sulfate proteoglycan in skeletal structure(Mary Ann Liebert, 2024) Basol, M.; Ersoz, E.; Özaktaş, Helin; Cakan-Akdogan, G.Article Citation - WoS: 5Citation - Scopus: 5A Microrna-Regulated Transcriptional State Defines Intratumoral Cd8+t Cells That Respond To Immunotherapy(Cell Press, 2025) Tang, William W.; Battistone, Ben; Bauer, Kaylyn M.; Weis, Allison M.; Barba, Cindy; Fadlullah, Muhammad Zaki Hidayatullah; O'Connell, Ryan M.The rising incidence of advanced-stage colorectal cancer (CRC) and poor survival outcomes necessitate new and effective therapies. Immune checkpoint inhibitors (ICIs), specifically anti-PD-1 therapy, show promise, yet clinical determinants of a positive response are suboptimal. Here, we identify microRNA-155 (miR-155) as necessary for CD8+ T cell-infiltrated tumors through an unbiased in vivo CRISPR-Cas9 screen identifying functional tumor antigen-specific CD8+ T cell-expressed microRNAs. T cell miR-155 is required for anti-PD-1 responses and for a vital intratumor CD8+ T cell differentiation cascade by repressing Ship-1, inhibiting Tcf-1 and stemness, and subsequently enhancing Cxcr6 expression, anti-tumor immunity, and effector functions. Based on an underlying miR-155-dependent CD8+ T cell transcriptional profile, we identify a gene signature that predicts ICI responses across 12 diverse cancers. Together, our findings support a model whereby miR155 serves as a central regulator of CD8+ T cell-dependent cancer immunity and ICI responses that may be leveraged for future therapeutics.Conference Object Investigation of the role of Wnt/β-catenin signaling in development of Alzheimer's disease in a zebrafish model of mmyloid-β toxicity(Wiley, 2024) Nazlı, Dilek; Ipekgil, D.; Poyraz, Y. K.; Catak, B.; Sahin, E. Turhanlar; Özhan, GüneşThe Wnt/β-catenin signaling pathway, an evolutionarily conserved and pivotal pathway associated with synapse formation in adulthood, plays a crucial role in Alzheimer's disease (AD). AD, marked by various pathologies, is primarily linked to the accumulation of extracellular beta-amyloid plaques. The interplay between this accumulation and disruptions in the Wnt/β-catenin signaling pathway triggers synaptic degeneration, resulting in synaptic dysfunction and AD progression. In this study, we modeled AD induced by the Aβ42 peptide using adult transgenic (6XTCF) zebrafish. To establish the zebrafish AD model, we employed cerebroventricular microinjection (CVMI) with the Aβ42 peptide. Fish, anesthetized prior to CVMI, were positioned on a stable platform, and the Aβ42 peptide was injected into the telencephalon region of the brain by a capillary needle. Brain samples were collected on 1, 3, 4, 7, and 14 days post-CVMI (dpi) to analyze changes in Aβ42 peptide accumulation, the immune system response, synaptic degeneration, apoptosis, and the expression of genes related to proliferation using qPCR and immunofluorescent staining. To examine the role of the Wnt/β-catenin signaling pathway in the molecular mechanism of AD development, fish exhibiting high levels of regeneration on days 7 and 14 were treated with the IWR-1 drug, which inhibits the Wnt/β-catenin signaling by stabilizing the Axin2 protein, thereby suppressing the regenerative response. Our results revealed that the AD model manifested on 3dpi, with the regenerative response reaching its peak on 7dpi and 14dpi. Treatment with IWR-1 resulted in increased Aβ42 accumulation, accelerated synaptic degeneration, and elevated cell deaths in fish where the Wnt signaling pathway was inhibited. In conclusion, our adult zebrafish AD model is poised to elucidate the molecular mechanisms connecting the Wnt signaling pathway and AD, thereby contributing to the development of alternative therapeutic approaches for AD patients.Article Citation - WoS: 1Citation - Scopus: 1Association Mapping of Plant Structure and Yield Traits in Faba Bean (vicia Faba L.)(John Wiley and Sons Inc., 2023) Abuzayed, M.A.; Baytar, A.A.; Yanar, E.G.; Doğanlar, Sami; Frary, AnneTens of thousands of faba bean accessions are available in germplasm collections throughout the world. Morphological characterization of these materials can enrich these collections and aid in the selection of genotypes for use in breeding programs. Results: In this study, 26 morphological characters were analyzed for 61 faba bean landraces and 53 cultivars over two seasons in Izmir, Turkey. The genotypes had high diversity for several yield traits including number of pods per plant, dry seed yield, and 100-seed weight. Association mapping was conducted for the morphological characters using 651 alleles from 100 simple sequence repeat (SSR) markers and a general linear model based on the Q matrix. A false discovery rate of 0.20 was used to test the significance of marker–trait associations resulting in 75 loci detected for 20 of the morphological characters (p ≤ 0.001). Conclusion: Overall, 44% of the quantitative trait loci (QTLs) were for seed traits, with 24%, 15%, and 17% of QTL identified for vegetative, inflorescence, and pod traits, respectively. The phenotypic data and marker–trait associations generated by this work can help breeding programs in the selection and improvement of faba bean. © 2023 Society of Chemical Industry.Article Citation - WoS: 6Epitranscriptomics M<sup>6</Sup>a Analyses Reveal Distinct M<sup>6</Sup>a Marks Under Tumor Necrosis Factor Α (tnf-Α) Apoptotic Conditions in Hela Cells(Wiley, 2024) Akçaöz Alasar, Azime; Tüncel, Özge; Sağlam, Buket; Gazaloğlu, Yasemin; Atbinek, Melis; Çağıral, Umut; Akgül, BünyaminTumor necrosis factor-alpha (TNF-alpha) is a ligand that induces both intrinsic and extrinsic apoptotic pathways in HeLa cells by modulating complex gene regulatory mechanisms. However, the full spectrum of TNF-alpha-modulated epitranscriptomic m(6)A marks is unknown. We employed a genomewide approach to examine the extent of m(6)A RNA modifications under TNF-alpha-modulated apoptotic conditions in HeLa cells. miCLIP-seq analyses revealed a plethora of m(6)A marks on 632 target mRNAs with an enrichment on 99 mRNAs associated with apoptosis. Interestingly, the m(6)A RNA modification patterns were quite different under cisplatin- and TNF-alpha-mediated apoptotic conditions. We then examined the abundance and translational efficiencies of several mRNAs under METTL3 knockdown and/or TNF-alpha treatment conditions. Our analyses showed changes in the translational efficiency of TP53INP1 mRNA based on the polysome profile analyses. Additionally, TP53INP1 protein amount was modulated by METTL3 knockdown upon TNF-alpha treatment but not CP treatment, suggesting the existence of a pathway-specific METTL3-TP53INP1 axis. Congruently, METLL3 knockdown sensitized HeLa cells to TNF-alpha-mediated apoptosis, which was also validated in a zebrafish larval xenograft model. These results suggest that apoptotic pathway-specific m(6)A methylation marks exist in cells and TNF-alpha-METTL3-TP53INP1 axis modulates TNF-alpha-mediated apoptosis in HeLa cells.Review Citation - WoS: 17Citation - Scopus: 16Engineering Periodontal Tissue Interfaces Using Multiphasic Scaffolds and Membranes for Guided Bone and Tissue Regeneration(Elsevier, 2024) Özkendir, Özge; Karaca, İlayda; Çullu, Selin; Yaşar, Hüsniye Nur,; Erdoğan, Oğulcan; Dikici, Serkan; Dikici, Betul AldemirPeriodontal diseases are one of the greatest healthcare burdens worldwide. The periodontal tissue compartment is an anatomical tissue interface formed from the periodontal ligament, gingiva, cementum, and bone. This multifaceted composition makes tissue engineering strategies challenging to develop due to the interface of hard and soft tissues requiring multiphase scaffolds to recreate the native tissue architecture. Multilayer constructs can better mimic tissue interfaces due to the individually tuneable layers. They have different characteristics in each layer, with modulation of mechanical properties, material type, porosity, pore size, morphology, degradation properties, and drug-releasing profile all possible. The greatest challenge of multilayer constructs is to mechanically integrate consecutive layers to avoid delamination, especially when using multiple manufacturing processes. Here, we review the development of multilayer scaffolds that aim to recapitulate native periodontal tissue interfaces in terms of physical, chemical, and biological characteristics. Important properties of multiphasic biodegradable scaffolds are highlighted and summarised, with design requirements, biomaterials, and fabrication methods, as well as post-treatment and drug/growth factor incorporation discussed.Letter Citation - WoS: 1Citation - Scopus: 1Evaluating Ethanol Concentrations Against Staphylococcus Spp: a Proposal for Improving Nosocomial Bacteria Control(Elsevier, 2024) Soyer, Ferda; Özdemir, Özgün Öykü; Polat, Bengi; Ekenel, Nil HazalDear Editor, Nosocomial infections originating from commonly encountered pathogenic bacteria, notably Staphylococcus species, persist as a prominent global public health issue. This phenomenon exerts consequential impacts on both the well-being of patients and the healthcare personnel within hospital environments. Hospital-acquired infections from common bacteria like Staphylococcus remain a global public health concern. The European Centre for Disease Prevention and Control reports prevalence rates of 4.5% in the USA and 7.1% in Europe [1]. An estimated 8.9 million healthcare-associated infections occur annually in European hospitals and long-term care facilities [1]. According to the World Health Organization, although 10% of patients get healthcare-associated infections, at least a 30% reduction can be achieved through adequate infection prevention and control [2]. The efficacy of disinfection methodologies employed in healthcare institutions assumes critical significance in mitigating this threat.Article Citation - WoS: 6Citation - Scopus: 5Epitranscriptomics M6a Analyses Reveal Distinct M6a Marks Under Tumor Necrosis Factor Α (tnf-Α) Apoptotic Conditions in Hela Cells(Wiley, 2024) Akçaöz Alasar, Azime; Tuncel, Özge; Sağlam, Buket; Gazaloğlu, Yasemin; Atbinek, Melis; Çağıral, Umut; İşcan, Evin; Özhan, Güneş; Akgül, BünyaminTumor necrosis factor-alpha (TNF-alpha) is a ligand that induces both intrinsic and extrinsic apoptotic pathways in HeLa cells by modulating complex gene regulatory mechanisms. However, the full spectrum of TNF-alpha-modulated epitranscriptomic m(6)A marks is unknown. We employed a genomewide approach to examine the extent of m(6)A RNA modifications under TNF-alpha-modulated apoptotic conditions in HeLa cells. miCLIP-seq analyses revealed a plethora of m(6)A marks on 632 target mRNAs with an enrichment on 99 mRNAs associated with apoptosis. Interestingly, the m(6)A RNA modification patterns were quite different under cisplatin- and TNF-alpha-mediated apoptotic conditions. We then examined the abundance and translational efficiencies of several mRNAs under METTL3 knockdown and/or TNF-alpha treatment conditions. Our analyses showed changes in the translational efficiency of TP53INP1 mRNA based on the polysome profile analyses. Additionally, TP53INP1 protein amount was modulated by METTL3 knockdown upon TNF-alpha treatment but not CP treatment, suggesting the existence of a pathway-specific METTL3-TP53INP1 axis. Congruently, METLL3 knockdown sensitized HeLa cells to TNF-alpha-mediated apoptosis, which was also validated in a zebrafish larval xenograft model. These results suggest that apoptotic pathway-specific m(6)A methylation marks exist in cells and TNF-alpha-METTL3-TP53INP1 axis modulates TNF-alpha-mediated apoptosis in HeLa cells.Article Blank Frame and Intensity Variation Distortion Detection and Restoration Pipeline for Phase-Contrast Microscopy Time-Lapse Images(Aves, 2024) Ucar, Mahmut; Iheme, Leonardo O.; Onal, Sevgi; Pesen-Okvur, Devrim; Yalcin-Ozuysal, Ozden; Toreyin, Behcet U.; Unay, DevrimIn this study, we propose a preprocessing pipeline for the detection and correction of distorted frames in time-lapse images obtained from phase-contrast microscopy. The proposed pipeline employs the average intensities of frames as a foundational element for the analysis. In order to evaluate the degree of correction required for intensity variance, a normalization technique is applied to the difference between the average intensity of a specific frame and the median average intensity of all frames within the study. Our restoration method increases the histogram similarity between the distorted and non-distorted frames, preserves trans-passing pixels in regions of interest, and mitigates the development of additional distortions. The efficacy of the proposed method was evaluated using 15 395 time-lapse image frames from 27 experiments using our own dataset and 830 time-lapse images from four different experiments obtained from the cell tracking challenge. The results of the validation demonstrate a high degree of numerical and visual accuracy of the proposed pipeline.Article Citation - WoS: 8Citation - Scopus: 8Canonical Wnt and Tgf-β/Bmp Signaling Enhance Melanocyte Regeneration but Suppress Invasiveness, Migration, and Proliferation of Melanoma Cells(Frontiers Media S.A., 2023) Katkat, Esra; Demirci, Yeliz; Heger, Guillaume; Karagülle, Doğa; Papatheodorou, Irene; Brazma, Alvis; Özhan, GüneşMelanoma is the deadliest form of skin cancer and develops from the melanocytes that are responsible for the pigmentation of the skin. The skin is also a highly regenerative organ, harboring a pool of undifferentiated melanocyte stem cells that proliferate and differentiate into mature melanocytes during regenerative processes in the adult. Melanoma and melanocyte regeneration share remarkable cellular features, including activation of cell proliferation and migration. Yet, melanoma considerably differs from the regenerating melanocytes with respect to abnormal proliferation, invasive growth, and metastasis. Thus, it is likely that at the cellular level, melanoma resembles early stages of melanocyte regeneration with increased proliferation but separates from the later melanocyte regeneration stages due to reduced proliferation and enhanced differentiation. Here, by exploiting the zebrafish melanocytes that can efficiently regenerate and be induced to undergo malignant melanoma, we unravel the transcriptome profiles of the regenerating melanocytes during early and late regeneration and the melanocytic nevi and malignant melanoma. Our global comparison of the gene expression profiles of melanocyte regeneration and nevi/melanoma uncovers the opposite regulation of a substantial number of genes related to Wnt signaling and transforming growth factor beta (TGF-beta)/(bone morphogenetic protein) BMP signaling pathways between regeneration and cancer. Functional activation of canonical Wnt or TGF-beta/BMP pathways during melanocyte regeneration promoted melanocyte regeneration but potently suppressed the invasiveness, migration, and proliferation of human melanoma cells in vitro and in vivo. Therefore, the opposite regulation of signaling mechanisms between melanocyte regeneration and melanoma can be exploited to stop tumor growth and develop new anti-cancer therapies.