Researcher: Küçük, Nazlı Ezgi Özkan
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Küçük, Nazlı Ezgi Özkan
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Publication Metadata only Clinicopathologic correlations of urinary proteomic and metabolomic analysis in patients with renal aa amyloidosis and membranous nephropathy(Oxford Univ Press, 2023) Ozbek, Deniz Aral; Koc, Sila; Yet, Idil; Kablan, Sevilay; Uner, Meral; Lay, Incilay; Yıldırım, Tolga; Yılmaz, Seref Rahmi; Altun, Bulent; Küçük, Nazlı Ezgi Özkan; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); ;Background and Aims AA Amyloidosis is a multisystemic amyloidosis subtype that develops on the background of various chronic inflammatory etiologies. Urinary omics studies have become a promising tool for elucidating pathophysiology and prognosis of glomerular diseases. However, no urinary omics analysis has been performed focusing on renal AA amyloidosis in literature to the best of our knowledge. Our main aim in this study is to perform a comparative urine proteomic and metabolomic analysis of recently diagnosed renal AA amyloidosis and to investigate the correlation of bioinformatic results with clinical and pathological data. Method Urine samples of 8 recently diagnosed AA amyloidosis (AA), 8 membranous nephropathy (MN) and 6 healthy control group patients were collected before kidney biopsy procedure. Proteomic analyzes were performed with nLC/Q-TOF MS/MS and metabolomic analyzes were performed by GC/MS in all patients. Biopsy specimens were scored according to glomerulosclerosis (G), tubular atrophy (TA) and interstitial fibrosis (IF) grades by two pathologists. Raw spectroscopic data was analyzed using MaxQuant and MS-DIAL programs for proteomic and metabolomic studies, respectively. Statistical analysis of the differences in molecules between study groups were performed with ANOVA and HSD-Tukey tests. Principal component (PCA) and heatmap analyzes were made in R language, while gene ontology (GO), network and functional enrichment analysis of bioinformatic results were performed with PANTHER, STRING and MetaboAnalyst databases. Results In comparison between AA and MN groups, median eGFR values tend to be lower in the AA group (67.6 vs 112 ml/min/1.73 m2 respectively, p = 0.08). Median 24-hour urine protein levels did not show statistically significant difference (9499 vs 9512 mg/day respectively, p = 0.9). Percentage of patients with moderate/severe IF/TA was higher and G score was tend to be in AA group compared to MN group (p values 0.02 and 0.07 for IF/TA and G scores, respectively). As a result of proteomic analysis, a total of 859 proteins were determined. Statistical analysis showed 51 proteins that were significantly differ in AA group compared to the control group. GO and functional enrichment analyzes showed that statistically most significant sub-domains were mainly related with cell-cell adhesion (Figure 1 & 2). In comparative analysis between AA and MN patients, uromodulin (UMOD) was lower in the AA group than in the MN group (log2FC -3.37), whereas ribonuclease 1 (RNASE1) and α-1-microglobulin/bikunin precursor protein (AMBP) were higher in the AA group (log2FC 3.41 and 3.07, respectively). In Spearman correlation analyzes, significant negative correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03) and between AMBP-eGFR (r = -0.69, p = 0.003) variables. Metabolomic analysis showed 9 metabolites that were significantly different between AA and other study groups. Myo-inositol and urate were higher in AA group compared to MN group, while D-mannitol and N-acetylglutamate were higher in AA group compared to the control group. Significant positive correlation independent of GFR was detected between RNASE1 and urate (r = 0.63, p = 0.01).Publication Metadata only Proteomics in cell division(Wiley, 2017) N/A; N/A; N/A; N/A; N/A; Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Kagiali, Zeynep Cansu Üretmen; Şentürk, Aydanur; Küçük, Nazlı Ezgi Özkan; Qureshi, Mohammad Haroon; PhD Student; PhD Student; Researcher; PhD Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; N/A; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; N/A; N/A; 105301Cell division requires a coordinated action of the cell cycle machinery, cytoskeletal elements, chromosomes, and membranes. Cell division studies have greatly benefitted from the mass spectrometry (MS)-based proteomic approaches for probing the biochemistry of highly dynamic complexes and their coordination with each other as a cell progresses into division. In this review, the authors first summarize a wide-range of proteomic studies that focus on the identification of sub-cellular components/protein complexes of the cell division machinery including kinetochores, mitotic spindle, midzone, and centrosomes. The authors also highlight MS-based large-scale analyses of the cellular components that are largely understudied during cell division such as the cell surface and lipids. Then, the authors focus on posttranslational modification analyses, especially phosphorylation and the resulting crosstalk with other modifications as a cell undergoes cell division. Combining proteomic approaches that probe the biochemistry of cell division components with functional genomic assays will lead to breakthroughs toward a systems-level understanding of cell division.Publication Metadata only Plasma proteomics identify potential severity biomarkers from COVID-19 associated network(Wiley-V C H Verlag Gmbh) N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Şahin, Ayşe Tuğçe; Yurtseven, Ali; Dadmand, Sina; Kuyucu, Gülin Özcan; Akarlar, Büşra; Küçük, Nazlı Ezgi Özkan; Şentürk, Aydanur; Ergönül, Önder; Can, Füsun; Tunçbağ, Nurcan; PhD Student; Master Student; Master Student; PhD Student; Other; Researcher; PhD Student; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; N/A; N/A; Graduate School of Sciences and Engineering; School of Medicine; School of Medicine; College of Engineering; College of Sciences; Koç Üniversitesi İş Bankası Enfeksiyon Hastalıkları Uygulama ve Araştırma Merkezi (EHAM) / Koç University İşbank Center for Infectious Diseases (KU-IS CID); Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; N/A; N/A; N/A; N/A; N/A; 110398; 103165; 245513; 105301Purpose: Coronavirus disease 2019 (COVID-19) continues to threaten public health globally. Severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection-dependent alterations in the host cell signaling network may unveil potential target proteins and pathways for therapeutic strategies. In this study, we aim to define early severity biomarkers and monitor altered pathways in the course of SARS-CoV-2 infection. Experimental Design: We systematically analyzed plasma proteomes of COVID-19 patients from Turkey by using mass spectrometry. Different severity grades (moderate, severe, and critical) and periods of disease (early, inflammatory, and recovery) are monitored. Significant alterations in protein expressions are used to reconstruct the COVID-19 associated network that was further extended to connect viral and host proteins. Results: Across all COVID-19 patients, 111 differentially expressed proteins were found, of which 28 proteins were unique to our study mainly enriching in immunoglobulin production. By monitoring different severity grades and periods of disease, CLEC3B, MST1, and ITIH2 were identified as potential early predictors of COVID-19 severity. Most importantly, we extended the COVID-19 associated network with viral proteins and showed the connectedness of viral proteins with human proteins. The most connected viral protein ORF8, which has a role in immune evasion, targets many host proteins tightly connected to the deregulated human plasma proteins. Conclusions and Clinical Relevance: Plasma proteomes from critical patients are intrinsically clustered in a distinct group than severe and moderate patients. Importantly, we did not recover any grouping based on the infection period, suggesting their distinct proteome even in the recovery phase. The new potential early severity markers can be further studied for their value in the clinics to monitor COVID-19 prognosis. Beyond the list of plasma proteins, our disease-associated network unravels altered pathways, and the possible therapeutic targets in SARS-CoV-2 infection by connecting human and viral proteins. Follow-up studies on the disease associated network that we propose here will be useful to determine molecular details of viral perturbation and to address how the infection affects human physiology.Publication Metadata only Labeling carboxyl groups of surface-exposed proteins provides an orthogonal approach for cell surface isolation(Amer Chemical Soc, 2018) Tan, Edwin; Mitchison, Timothy; N/A; N/A; Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Küçük, Nazlı Ezgi Özkan; Şanal, Erdem; Researcher; PhD Student; Faculty Member; N/A; Graduate School of Sciences and Engineering; College of Sciences; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; 105301Quantitative profiling of cell surface proteins is critically important for the understanding of cell-cell communication, signaling, tissue development, and homeostasis. Traditional proteomics methods are challenging for cell surface proteins due to their hydrophobic nature and low abundance, necessitating alternative methods to efficiently identify and quantify this protein group. Here we established carboxyl reactive biotinylation for selective and efficient biotinylation and isolation of surface-exposed proteins of living cells. We assessed the efficiency of carboxyl-reactive biotinylation for plasma membrane proteins by comparing it with a well-established protocol, amine-reactive biotinylation, using SILAC (stable isotope labeling in cell culture). Our results show that carboxyl-reactive biotinylation of cell surface proteins is both more selective and more efficient than amine-reactive biotinylation. We conclude that it is a useful approach, which is partially orthogonal to amine-reactive biotinylation, allowing us to cast a wider net for a comprehensive profiling of cell surface proteins.Publication Metadata only Quantitative comparison of a human cancer cell surface proteome between interphase and mitosis(Wiley, 2015) Toyoda, Yusuke; Renard, Bernhard Y.; Mollaoglu, Gurkan; Poser, Ina; Timm, Wiebke; Hyman, Anthony A.; Mitchison, Timothy J.; Steen, Judith A.; Department of Molecular Biology and Genetics; N/A; N/A; N/A; N/A; Department of Molecular Biology and Genetics; Qureshi, Mohammad Haroon; Mollaoğlu, Gürkan; Küçük, Nazlı Ezgi Özkan; Bülbül, Selda; Faculty Member; PhD Student; Master Student; Researcher; Master Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; N/A; Graduate School of Sciences and Engineering; 105301; N/A; N/A; N/A; N/AThe cell surface is the cellular compartment responsible for communication with the environment. The interior of mammalian cells undergoes dramatic reorganization when cells enter mitosis. These changes are triggered by activation of the CDK1 kinase and have been studied extensively. In contrast, very little is known of the cell surface changes during cell division. We undertook a quantitative proteomic comparison of cell surface-exposed proteins in human cancer cells that were tightly synchronized in mitosis or interphase. Six hundred and twenty-eight surface and surface-associated proteins in HeLa cells were identified; of these, 27 were significantly enriched at the cell surface in mitosis and 37 in interphase. Using imaging techniques, we confirmed the mitosis-selective cell surface localization of protocadherin PCDH7, a member of a family with anti-adhesive roles in embryos. We show that PCDH7 is required for development of full mitotic rounding pressure at the onset of mitosis. Our analysis provided basic information on how cell cycle progression affects the cell surface. It also provides potential pharmacodynamic biomarkers for anti-mitotic cancer chemotherapy.Publication Metadata only Cell cycle-dependent palmitoylation of protocadherin 7 by ZDHHC5 promotes successful cytokinesis(Company of Biologists Ltd, 2023) N/A; Department of Molecular Biology and Genetics; Department of Physics; N/A; N/A; Department of Molecular Biology and Genetics; Department of Physics; Kiraz, Alper; Bavili, Nima; Kamacıoğlu, Altuğ; Küçük, Nazlı Ezgi Özkan; Qureshi, Mohammad Haroon; Yapıcı, Gamze Nur; Yiğit, Berfu Nur; Değirmenci, Beste Senem; Faculty Member; Faculty Member; PhD Student; Master Student; Researcher; PhD Student; PhD Student; PhD Student; PhD Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Sciences; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; N/A; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; 105301; 22542; N/A; N/A; N/A; N/A; N/A; N/A; N/ACell division requires dramatic reorganization of the cell cortex, which is primarily driven by the actomyosin network. We previously reported that protocadherin 7 (PCDH7) gets enriched at the cell surface during mitosis, which is required to build up the full mitotic rounding pressure. Here, we report that PCDH7 interacts with and is palmitoylated by the palmitoyltransferase, ZDHHC5. PCDH7 and ZDHHC5 colocalize at the mitotic cell surface and translocate to the cleavage furrow during cytokinesis. The localization of PCDH7 depends on the palmitoylation activity of ZDHHC5. Silencing PCDH7 increases the percentage of multinucleated cells and the duration of mitosis. Loss of PCDH7 expression correlates with reduced levels of active RhoA and phospho-myosin at the cleavage furrow. This work uncovers a palmitoylation-dependent translocation mechanism for PCDH7, which contributes to the reorganization of the cortical cytoskeleton during cell division.Publication Open Access AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation(BioMed Central, 2021) Philpott, Martin; Oppermann, Udo; Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Önder, Tamer Tevfik; Uğurlu Çimen, Deniz; Sevinç, Kenan; Küçük, Nazlı Ezgi Özkan; Özçimen, Burcu; Demirtaş, Deniz; Enüstün, Eray; Faculty Member; Faculty Member; PhD Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; 42946; 105301; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/ABackground: the histone H3 lysine 79 (H3K79) methyltransferase DOT1L is a key chromatin-based barrier to somatic cell reprogramming. However, the mechanisms by which DOT1L safeguards cell identity and somatic-specific transcriptional programs remain unknown. Results: we employed a proteomic approach using proximity-based labeling to identify DOT1L-interacting proteins and investigated their effects on reprogramming. Among DOT1L interactors, suppression of AF10 (MLLT10) via RNA interference or CRISPR/Cas9, significantly increases reprogramming efficiency. In somatic cells and induced pluripotent stem cells (iPSCs) higher order H3K79 methylation is dependent on AF10 expression. In AF10 knock-out cells, re-expression wild-type AF10, but not a DOT1L binding-impaired mutant, rescues overall H3K79 methylation and reduces reprogramming efficiency. Transcriptomic analyses during reprogramming show that AF10 suppression results in downregulation of fibroblast-specific genes and accelerates the activation of pluripotency-associated genes. Conclusions: our findings establish AF10 as a novel barrier to reprogramming by regulating H3K79 methylation and thereby sheds light on the mechanism by which cell identity is maintained in somatic cells.