Researcher:
Uyulur, Fırat

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Fırat

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Uyulur

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Uyulur, Fırat

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2019 - 201922020 - 20221

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Researcher Of Publications: search.filters.isAuthorOfPublication.5ab52bba-6f4c-4bfb-a733-dfa434e28605

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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
    EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities
    (Nature Portfolio, 2022) Philpott, Martin; Cribbs, Adam P.; Kung, Sonia H.Y; Bayram, Özlem Yedier; Gökbayrak, Bengül; Kayabölen, Alişan; Aksu, Ali Cenk; Cavga, Ayşe Derya; Cingöz, Ahmet; Kala, Ezgi Yağmur; Karabıyık, Göktuğ; Esin, Beril; Morova, Tunç; Uyulur, Fırat; Önder, Tuğba Bağcı; Syed, Hamzah; Lack, Nathan Alan; Önder, Tamer Tevfik; PhD Student; Faculty Member; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 184359; 318138; 120842; 42946
    Dysregulation of the epigenome due to alterations in chromatin modifier proteins commonly contribute to malignant transformation. To interrogate the roles of epigenetic modifiers in cancer cells, we generated an epigenome-wide CRISPR-Cas9 knockout library (EPIKOL) that targets a wide-range of epigenetic modifiers and their cofactors. We conducted eight screens in two different cancer types and showed that EPIKOL performs with high efficiency in terms of sgRNA distribution and depletion of essential genes. We discovered novel epigenetic modifiers that regulate triple-negative breast cancer (TNBC) and prostate cancer cell fitness. We confirmed the growth-regulatory functions of individual candidates, including SS18L2 and members of the NSL complex (KANSL2, KANSL3, KAT8) in TNBC cells. Overall, we show that EPIKOL, a focused sgRNA library targeting similar to 800 genes, can reveal epigenetic modifiers that are essential for cancer cell fitness under in vitro and in vivo conditions and enable the identification of novel anti-cancer targets. Due to its comprehensive epigenome-wide targets and relatively high number of sgRNAs per gene, EPIKOL will facilitate studies examining functional roles of epigenetic modifiers in a wide range of contexts, such as screens in primary cells, patient-derived xenografts as well as in vivo models.
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    PublicationOpen Access
    The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma
    (Nature Publishing Group (NPG), 2019) Gezen, Melike; Tolay, Nazife; Erman, Batu; Dunford, James; Oppermann, Udo; N/A; Department of Industrial Engineering; Department of Molecular Biology and Genetics; N/A; Uyulur, Fırat; Gönen, Mehmet; Önder, Tuğba Bağcı; Özyerli, Ezgi; Sur, İlknur Erdem; Şeker-Polat, Fidan; Cingöz, Ahmet; Kayabölen, Alişan; Kahya, Zeynep; Faculty Member; Department of Industrial Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Engineering; School of Medicine; Graduate School of Health Sciences; N/A; 237468; 184359; N/A; N/A; N/A; N/A; N/A; N/A
    Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radio-therapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. TRAIL (TNF Related Apoptosis Inducing Ligand) is a potent anti-cancer agent that can induce apoptosis selectively in cancer cells. GBM cells frequently develop resistance to TRAIL which renders clinical application of TRAIL therapeutics inefficient. In this study, we undertook a chemical screening approach using a library of epigenetic modifier drugs to identify compounds that could augment TRAIL response. We identified the fungal metabolite chaetocin, an inhibitor of histone methyl transferase SUV39H1, as a novel TRAIL sensitizer. Combining low subtoxic doses of chaetocin and TRAIL resulted in very potent and rapid apoptosis of GBM cells. Chaetocin also effectively sensitized GBM cells to further pro-apoptotic agents, such as FasL and BH3 mimetics. Chaetocin mediated apoptosis sensitization was achieved through ROS generation and consequent DNA damage induction that involved P53 activity. Chaetocin induced transcriptomic changes showed induction of antioxidant defense mechanisms and DNA damage response pathways. Heme Oxygenase 1 (HMOX1) was among the top upregulated genes, whose induction was ROS-dependent and HMOX1 depletion enhanced chaetocin mediated TRAIL sensitization. Finally, chaetocin and TRAIL combination treatment revealed efficacy in vivo. Taken together, our results provide a novel role for chaetocin as an apoptosis priming agent and its combination with pro-apoptotic therapies might offer new therapeutic approaches for GBMs.