Researcher:
Sevinç, Kenan

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PhD Student

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Kenan

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Sevinç

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Sevinç, Kenan

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2016 - 201932020 - 20223

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Researcher Of Publications: search.filters.isAuthorOfPublication.11b3b0ae-5571-4ff1-844e-e589467a2d6c

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Now showing 1 - 6 of 6
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    Identification of novel molecular players of GBM cell dispersal through an in vitro profiling approach
    (Oxford Univ Press, 2016) Gümüş, Zeynep Hülya; N/A; N/A; N/A; N/A; Department of Industrial Engineering; N/A; Şeker-Polat, Fidan; Erkent, Mahmut Alp; Ergüder, Nazlı; Sevinç, Kenan; Gönen, Mehmet; Önder, Tuğba Bağcı; Phd Student; Undergraduate Student; Undergraduate Student; Phd Student; Faculty Member; Faculty Member; Department of Industrial Engineering; Graduate School of Health Sciences; School of Medicine; School of Medicine; Graduate School of Sciences and Engineering; College of Engineering; School of Medicine; N/A; N/A; N/A; N/A; 237468; 184359
    Glioblastoma multiforme (GBM) is the most common and aggressive type of gliomas with a mean survival of 1 year after diagnosis. A major obstacle in treating GBMs is extensive tumor cell infiltration into the surrounding brain. Despite tumor resection and combined therapy, recurrence occurs in the vicinity of the resection margin due to individual cells that dispersed out of the primary tumor, therefore; developing novel therapies that target tumor cell dispersal is of high priority. The goal of this project is to identify genes that are differentially regulated during GBM cell dispersal and to validate their function in in vitro models of dispersal. In this project, we have used an in vitro model of cell motility whereby the dynamics of GBM cell dispersal can be monitored in real-time and quantitated. Accordingly, we isolated motile/migratory/dispersive cells from non-motile/core cells and used these cells for investigating the genes that are differentially regulated during different phases of cell movement by using RNA sequencing. Analysis of the sequencing experiments showed the presence of many differentially expressed genes in motile vs non-motile cells. Most of the genes that have the highest expression in motile cells compared to non-motile ones were linked to epithelial to mesenchymal transition and cell motility based on our pathway and gene set enrichment analyses. Our current focus is on five different candidate genes: CTGF, CYR61, SERPINE1, INHBA and PTX3. Among these, the expression of SERPINE1, a serine protease inhibitor, had predictive value for overall survival of gliomas and therefore is an interesting therapeutic candidate. Currently, we are conducting loss-of-function and gain-of function experiments targeting these genes. Together, these studies have the potential to discover novel molecular players of GBM cell dispersal and open up new avenues for designing new therapeutic strategies against the invasive phenotype of otherwise untreatable malignant GBMs.
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    Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming
    (Nature Publishing Group (NPG), 2019) Cribbs, Adam P.; Philpott, Martin; Dunford, James E.; Ari, Sule; Oppermann, Udo; N/A; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Önder, Tamer Tevfik; Ebrahimi, Ayyub A.; Sevinç, Kenan; Sevinç, Gülben Gürhan; Uyulur, Fırat; Morova, Tunç; Göklemez, Sencer; Faculty Member; Researcher; PhD Student; PhD Student; Undergraduate Student; Master Student; Undergraduate Student; Department of Molecular Biology and Genetics; School of Medicine; School of Medicine; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; College of Sciences; Graduate School of Sciences and Engineering; School of Medicine; 42946; 381072; N/A; N/A; N/A; N/A; N/A
    Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.
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    PublicationOpen Access
    Perspectives on current models of Friedreich's ataxia
    (Frontiers, 2022) Department of Molecular Biology and Genetics; Önder, Tamer Tevfik; Kelekçi, Simge; Yıldız, Abdullah Burak; Sevinç, Kenan; Uğurlu Çimen, Deniz; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Sciences and Engineering; 42946; N/A; N/A; N/A; N/A
    Friedreich's ataxia (FRDA, OMIM#229300) is the most common hereditary ataxia, resulting from the reduction of frataxin protein levels due to the expansion of GAA repeats in the first intron of the FXN gene. Why the triplet repeat expansion causes a decrease in Frataxin protein levels is not entirely known. Generation of effective FRDA disease models is crucial for answering questions regarding the pathophysiology of this disease. There have been considerable efforts to generate in vitro and in vivo models of FRDA. In this perspective article, we highlight studies conducted using FRDA animal models, patient-derived materials, and particularly induced pluripotent stem cell (iPSC)-derived models. We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.
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    PublicationOpen Access
    Robust, long-term culture of endoderm-derived hepatic organoids for disease modeling
    (Cell Press, 2019) Akbari, Soheil; Ersoy, Nevin; Başak, Onur; Kaplan, Kübra; Bağrıyanık, Alper; Arslan, Nur; Erdal, Esra; Department of Molecular Biology and Genetics; Önder, Tamer Tevfik; Sevinç, Gülben Gürhan; Özçimen, Burcu; Enüstün, Eray; Şengün, Berke; Özel, Erkin; Sevinç, Kenan; Faculty Member; PhD Student; Undergraduate Student; Department of Molecular Biology and Genetics; School of Medicine; Graduate School of Health Sciences; 42946; N/A; N/A; N/A; N/A; N/A; N/A
    Organoid technologies have become a powerful emerging tool to model liver diseases, for drug screening, and for personalized treatments. These applications are, however, limited in their capacity to generate functional hepatocytes in a reproducible and efficient manner. Here, we generated and characterized the hepatic organoid (eHEPO) culture system using human induced pluripotent stem cell (iPSC)-derived EpCAM-positive endodermal cells as an intermediate. eHEPOs can be produced within 2 weeks and expanded long term (>16 months) without any loss of differentiation capacity to mature hepatocytes. Starting from patient-specific iPSCs, we modeled citrullinemia type 1, a urea cycle disorder caused by mutations in the argininosuccinate synthetase (ASST) enzyme. The disease-related ammonia accumulation phenotype in eHEPOs could be reversed by the overexpression of the wild-type ASS1 gene, which also indicated that this model is amenable to genetic manipulation. Thus, eHEPOs are excellent unlimited cell sources to generate functional hepatic organoids in a fast and efficient manner.
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    BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming
    (Elsevier, 2022) Philpott, M.; Cribbs, A.P.; Dunford, J.E.; Sigua, L.H.; Qi, J.; Oppermann, U.; Department of Molecular Biology and Genetics; N/A; Sevinç, Kenan; Cavga, Ayşe Derya; Kelekçi, Simge; Can, Hazal; Yıldız, Abdullah Burak; Yılmaz, Alperen; Ayar, Enes Sefa; Ata, Deniz; Önder, Tamer Tevfik; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Sciences and Engineering; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 42946
    Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes to silence existing cell-type-specific genes and activate pluripotency genes. ATP-dependent chromatin remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of recently identified Bromodomain-containing protein 9 (BRD9) and the associated non-canonical BRG1-associated factors (ncBAF) complex in reprogramming remains unknown. Here, we show that genetic or chemical inhibition of BRD9, as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, increase human somatic cell reprogramming efficiency and can replace KLF4 and c-MYC. We find that BRD9 is dispensable for human induced pluripotent stem cells under primed but not under naive conditions. Mechanistically, BRD9 inhibition downregulates fibroblast-related genes and decreases chromatin accessibility at somatic enhancers. BRD9 maintains the expression of transcriptional regulators MN1 and ZBTB38, both of which impede reprogramming. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers chromatin-based barriers to reprogramming.
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    PublicationOpen 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; Önder, Tamer Tevfik; Uğurlu Çimen, Deniz; Sevinç, Kenan; Küçük, Nazlı Ezgi Özkan; Özçimen, Burcu; Demirtaş, Deniz; Enüstün, Eray; Faculty Member; Faculty Member; PhD Student; Department of Molecular Biology and Genetics; 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/A
    Background: 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.