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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease(BioMed Central, 2016) Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena; N/A; Department of Molecular Biology and Genetics; Zeybel, Müjdat; Karahüseyinoğlu, Serçin; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; 214694; 110772Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium beadarrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies. Conclusions: Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. Cpg methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.Publication Open Access A proximity mapping journey into the biology of the mammalian centrosome/cilium complex(Multidisciplinary Digital Publishing Institute (MDPI), 2020) Department of Molecular Biology and Genetics; Arslanhan, Melis Dilara; Gülensoy, Dila; Karalar, Elif Nur Fırat; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 206349The mammalian centrosome/cilium complex is composed of the centrosome, the primary cilium and the centriolar satellites, which together regulate cell polarity, signaling, proliferation and motility in cells and thereby development and homeostasis in organisms. Accordingly, deregulation of its structure and functions is implicated in various human diseases including cancer, developmental disorders and neurodegenerative diseases. To better understand these disease connections, the molecular underpinnings of the assembly, maintenance and dynamic adaptations of the centrosome/cilium complex need to be uncovered with exquisite detail. Application of proximity-based labeling methods to the centrosome/cilium complex generated spatial and temporal interaction maps for its components and provided key insights into these questions. In this review, we first describe the structure and cell cycle-linked regulation of the centrosome/cilium complex. Next, we explain the inherent biochemical and temporal limitations in probing the structure and function of the centrosome/cilium complex and describe how proximity-based labeling approaches have addressed them. Finally, we explore current insights into the knowledge we gained from the proximity mapping studies as it pertains to centrosome and cilium biogenesis and systematic characterization of the centrosome, cilium and centriolar satellite interactomes.Publication Open Access Genome-wide analysis reveals regional patterns of drift, structure, and gene flow in longfin smelt (Spirinchus thaleichthys) in the northeastern Pacific(Canadian Science Publishing, 2021) Hobbs, James; Baxter, Randall; Lewis, Levi S.; Benjamin, Alyssa; Finger, Amanda J.; Department of Molecular Biology and Genetics; Sağlam, İsmail Kudret; Faculty Member; Department of Molecular Biology and Genetics; College of Sciences; 168783The southernmost stock of longfin smelt (Spirinchus thaleichthys) is approaching extirpation in the San Francisco Estuary (SFE); however, patterns of genetic structure, diversity and gene flow which are vital for management are poorly understood in this species. Here, we use genome-wide data to evaluate population structure of longfin smelt across a broad latitudinal scale across estuaries ranging from the SFE to Yakutat Bay and Lake Washington, and fine scale within the Fraser River and the SFE. Results indicate high genetic structure between major estuaries, fine-scale structure within the Fraser River, and low levels of structure within the SFE. Genetic structure was more pronounced between northern estuaries whereas southern estuaries showed shared ancestry and ongoing gene flow, most notably unidirectional northward migration out of the SFE. Furthermore, we detected signatures of local adaptation within the Fraser River and the Skeena River estuaries. Taken together, our results identify broad patterns of genetic diversity in longfin smelt shaped by co-ancestry, unidirectional migration and local adaptation. Results also suggest that the SFE population is genetically distinct from northernmost populations and an important source for maintaining nearby populations.Publication Open Access The influence of ecological traits and environmental factors on the co-occurrence patterns of birds on islands worldwide(Wiley, 2020) Sato, Eri; Kusumoto, Buntarou; Kubota, Yasuhiro; Murakami, Masashi; Department of Molecular Biology and Genetics; Şekercioğlu, Çağan Hakkı; Faculty Member; Department of Molecular Biology and Genetics; College of SciencesTo understand the mechanisms shaping global species diversity patterns, we focused on species assembly of bird communities on islands, which are ideal for detecting ecological and historical processes. We tested the hypotheses that species traits and island environments interactively shape the phylogenetic structure of island bird assemblages through a variety of ecological processes: habitat filtering, in-situ speciation, extinction, dispersal limitation and competitive exclusion. We assessed the effects of species ecological traits and environment factors on the phylogenetic fields, which defined as phylogenetic distance between individual bird species and co-occurred species within each island, using phylogenetic generalized linear mixed models. Climate and isolation were the most important factors driving the co-occurrence patterns of island bird species: the species' phylogenetic fields were significantly clustered on tropical and/or isolated islands. We also found that the phylogenetic fields strongly correlated with the ecological traits especially for the diet and habitat preferences: the phylogenetic fields tended to over-disperse for granivores and species inhabiting in wetlands or coasts, while frugivores showed clustered phylogenetic fields. Moreover, mobility and body size had substantial effects on species assemblages: long-distance dispersers had clustered phylogenetic fields and small-bodied species showed overdispersed phylogenetic fields.Publication Open Access In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials(Taylor _ Francis, 2020) Asar, Sinan; Okyar, Alper; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Özcan, Onur; Barış, İbrahim; Kavaklı, İbrahim Halil; Researcher; Teaching Faculty; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; N/A; 111629; 40319Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL(pro)) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL(pro)based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients.Publication Open Access ENKD1 is a centrosomal and ciliary microtubule-associated protein important for primary cilium content regulation(Wiley, 2022) Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Tiryaki, Fatmanur; Deretic, Jovana; Karalar, Elif Nur Fırat; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 206349Centrioles and cilia are conserved, microtubule-based structures critical for cell function and development. Their dysfunction causes cancer and developmental disorders. How microtubules are organized into ordered structures by microtubule-associated proteins (MAPs) and tubulin modifications is best understood during mitosis but is largely unexplored for the centrioles and the ciliary axoneme, which are composed of stable microtubules that maintain their length at a steady-state. In particular, we know little about the identity of the centriolar and ciliary MAPs and how they work together during the assembly and maintenance of the cilium and centriole. Here, we identified the Enkurin domain containing 1 (ENKD1) as a component of the centriole wall and the axoneme in mammalian cells and showed that it has extensive proximity interactions with these compartments and MAPs. Using in vitro and cellular assays, we found that ENKD1 is a new MAP that regulates microtubule organization and stability. Consistently, we observed an increase in tubulin polymerization and microtubule stability, as well as disrupted microtubule organization in ENKD1 overexpression. Cells depleted for ENKD1 were defective in ciliary length and content regulation and failed to respond to Hedgehog pathway activation. Together, our results advance our understanding of the functional and regulatory relationship between MAPs and the primary cilium.Publication Open Access Plasmon-coupled photocapacitor neuromodulators(American Chemical Society (ACS), 2020) Ülgüt, Burak; Çetin, Arif E.; N/A; N/A; Department of Molecular Biology and Genetics; Department of Electrical and Electronics Engineering; Department of Chemical and Biological Engineering; Melikov, Rustamzhon; Srivastava, Shashi Bhushan; Karatüm, Onuralp; Doğru-Yüksel, Itır Bakış; Jalali, Houman Bahmani; Sadeghi, Sadra; Dikbaş, Uğur Meriç; Kavaklı, İbrahim Halil; Nizamoğlu, Sedat; PhD Student; Researcher; PhD Student; PhD Student; Master Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Electrical and Electronics Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Sciences; College of Engineering; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 40319; 130295Efficient transduction of optical energy to bioelectrical stimuli is an important goal for effective communication with biological systems. For that, plasmonics has a significant potential via boosting the light-matter interactions. However, plasmonics has been primarily used for heat-induced cell stimulation due to membrane capacitance change (i.e., optocapacitance). Instead, here, we demonstrate that plasmonic coupling to photocapacitor biointerfaces improves safe and efficacious neuromodulating displacement charges for an average of 185% in the entire visible spectrum while maintaining the faradic currents below 1%. Hot-electron injection dominantly leads the enhancement of displacement current in the blue spectral window, and the nanoantenna effect is mainly responsible for the improvement in the red spectral region. The plasmonic photocapacitor facilitates wireless modulation of single cells at three orders of magnitude below the maximum retinal intensity levels, corresponding to one of the most sensitive optoelectronic neural interfaces. This study introduces a new way of using plasmonics for safe and effective photostimulation of neurons and paves the way toward ultrasensitive plasmon-assisted neurostimulation devices.Publication Open Access Generation of integration-free induced pluripotent stem cells from a patient with Familial Mediterranean Fever (FMF)(Elsevier, 2015) Gül, Ahmet; Department of Molecular Biology and Genetics; Fidan, Kerem; Kavaklıoğlu, Gülnihal; Ebrahimi, Ayyub A.; Özlü, Can; Ay, Nur Zeynep; Ruacan, Ayşe Arzu; Önder, Tamer Tevfik; Master Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; Graduate School of Sciences and Engineering; N/A; N/A; N/A; N/A; N/A; 38250; 42946Fibroblasts from a Familial Mediterranean Fever (FMF) patient were reprogrammed with episomal vectors by using the Neon Transfection System for the generation of integration-free induced pluripotent stem cells (iPSCs). The resulting iPSC line was characterized to determine the expression of pluripotency markers, proper differentiation into three germ layers, the presence of normal chromosomal structures as well as the lack of genomic integration. A homozygous missense mutation in the MEFV gene (p.Met694Val), which lead to typical FMF phenotype, was shown to be present in the generated iPSC line.Publication Open Access A bacteria-derived tail anchor localizes to peroxisomes in yeast and mammalian cells(Nature Publishing Group (NPG), 2018) Seferoğlu, Ayşe Bengisu; Department of Molecular Biology and Genetics; Dunn, Cory David; Keskin, Abdurrahman; Akdoğan, Emel; Lutfullahoglu-Bal, Guleycan; Department of Molecular Biology and Genetics; College of SciencesProkaryotes can provide new genetic information to eukaryotes by horizontal gene transfer (HGT), and such transfers are likely to have been particularly consequential in the era of eukaryogenesis. Since eukaryotes are highly compartmentalized, it is worthwhile to consider the mechanisms by which newly transferred proteins might reach diverse organellar destinations. Toward this goal, we have focused our attention upon the behavior of bacteria-derived tail anchors (TAs) expressed in the eukaryote Saccharomyces cerevisiae. In this study, we report that a predicted membrane-associated domain of the Escherichia coli YgiM protein is specifically trafficked to peroxisomes in budding yeast, can be found at a pre-peroxisomal compartment (PPC) upon disruption of peroxisomal biogenesis, and can functionally replace an endogenous, peroxisome-directed TA. Furthermore, the YgiM(TA) can localize to peroxisomes in mammalian cells. Since the YgiM(TA) plays no endogenous role in peroxisomal function or assembly, this domain is likely to serve as an excellent tool allowing further illumination of the mechanisms by which TAs can travel to peroxisomes. Moreover, our findings emphasize the ease with which bacteria-derived sequences might target to organelles in eukaryotic cells following HGT, and we discuss the importance of flexible recognition of organelle targeting information during and after eukaryogenesis.Publication Open Access Temporal and compartment-specific signals coordinate mitotic exit with spindle position(Nature Publishing Group (NPG), 2017) Khmelinskii, Anton; Duenas-Sanchez, Rafael; Kurtulmus, Bahtiyar; Knop, Michael; Pereira, Gislene; Department of Molecular Biology and Genetics; Çaydaşı, Ayşe Koca; Faculty Member; Department of Molecular Biology and Genetics; College of Sciences; 252978The spatiotemporal control of mitotic exit is crucial for faithful chromosome segregation during mitosis. In budding yeast, the mitotic exit network (MEN) drives cells out of mitosis, whereas the spindle position checkpoint (SPOC) blocks MEN activity when the anaphase spindle is mispositioned. How the SPOC operates at a molecular level remains unclear. Here, we report novel insights into how mitotic signalling pathways orchestrate chromosome segregation in time and space. We establish that the key function of the central SPOC kinase, Kin4, is to counterbalance MEN activation by the cdc fourteen early anaphase release (FEAR) network in the mother cell compartment. Remarkably, Kin4 becomes dispensable for SPOC function in the absence of FEAR. Cells lacking both FEAR and Kin4 show that FEAR contributes to mitotic exit through regulation of the SPOC component Bfa1 and the MEN kinase Cdc15. Furthermore, we uncover controls that specifically promote mitotic exit in the daughter cell compartment.