Researcher:
Önder, Tamer Tevfik

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Tamer Tevfik

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Önder

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Önder, Tamer Tevfik

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Now showing 1 - 10 of 33
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    Publication
    NLRP7's key role in primate trophoblast differentiation
    (Amer Soc Cell Biology, 2017) Garipcan, A.; Özören, Nesrin; N/A; Özçimen, Burcu; Önder, Tamer Tevfik; Phd Student; Faculty Member; Graduate School of Sciences and Engineering; School of Medicine; 316273; 42946
    N/A
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    Publication
    Epigenetic modifications of androgen receptor signaling in castration resistant prostate cancer (CRPC)
    (Elsevier Sci Ltd, 2014) Saraç, Hilal; Toparlak, Ömer Duhan; Kaplan, Anıl; Ebrahimi, Ayyub A.; Önder, Tuğba Bağcı; Önder, Tamer Tevfik; Lack, Nathan Alan; PhD Student; Other; Undergraduate Student; Researcher; Faculty Member; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; N/A; 381072; 184359; 42946; 120842
    Introduction: Prostate cancer is one of the most common forms of cancer in Turkish and European men. For those patients with late-stage prostate cancer, androgen depletion therapy is current standard treatment. While initially successful, almost all patients eventually develop resistance against this treatment. Once the cancer reaches this advanced, progressive form, it is termed castration resistant prostate cancer (CRPC). Whereas the progression mechanisms of CRPC are poorly understood, it has been shown that in CRPC patients, the androgen receptor (AR) is still active despite undetectable androgen levels. Since AR signaling is important in the progression and growth of prostate cancer, understanding how AR mediated signaling occurs in CRPC is critical to more efficient treatment of this recurrent disease. Material and Methods: There are several possible causes for this conversion from androgen-sensitive to androgen-independent prostate cancer. Previous work has demonstrated that epigenetic modifiers such as EZH2 and LSD1 can mediate the sensitization of androgen receptor in CRPC. However, only a small subset of epigenetic modifiers has been characterized. To better understand the role of histone modification on CRPC, we conducted a large scale shRNA screen of epigenetic modifying enzymes to identify those genes that prevent androgen-independent growth. Results and Discussion: From this screen several hit genes have been found that cause a reversion of androgen-independent to androgen-dependent prostate cancer. The shRNA knock-down of these hit genes was confirmed by western blot and qRT-PCR. We are currently characterizing how these epigenetic modifiers affect androgen-receptor mediated signalling. Conclusion: These results will offer new insight into the role of epigenetic modifiers in nuclear receptor signalling.
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    Genome-wide chromatin state transitions associated with developmental and environmental cues
    (CELL PRESS, 2013) Zhu, Jiang; Adli, Mazhar; Zou, James Y.; Verstappen, Griet; Coyne, Michael; Zhang, Xiaolan; Durham, Timothy; Miri, Mohammad; Deshpande, Vikram; De Jager, Philip L.; Bennett, David A.; Houmard, Joseph A.; Muoio, Deborah M.; Camahort, Ray; Cowan, Chad A.; Meissner, Alexander; Epstein, Charles B.; Shoresh, Noam; Bernstein, Bradley E.; N/A; Önder, Tamer Tevfik; Faculty Member; School of Medicine; 42946
    Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here, we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized compaction. Exposure to serum in vitro triggers a distinct transition that involves de novo establishment of domains with features of constitutive heterochromatin. We describe how these global chromatin state transitions relate to chromosome and nuclear architecture, and discuss their implications for lineage fidelity, cellular senescence, and reprogramming.
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    Mechanisms of somatic cell reprogramming
    (Humana Press Inc, 2013) N/A; N/A; Önder, Tamer Tevfik; Faculty Member; School of Medicine; 42946
    Generation of induced pluripotent stem cells (iPSCs) from somatic cell types has revolutionized the field of stem cell biology and opened the way for production of disease- and patient-specific stem cells which have tremendous potential for regenerative medicine. Despite the rapid progress and improvement in iPSC-derivation techniques, transcription factor-based reprogramming remains an inefficient and poorly understood process. Successful reprogramming requires the completion of a number of rate-limiting steps that include avoiding senescence, mesenchymal-epithelial transition, and activation of endogenous pluripotency genes. It has also become clear that the global epigenetic landscape of the somatic cell types is completely overhauled during acquisition of pluripotency. The epigenetic state is largely determined by the deposition of chromatin marks which include histone tail modifications and DNA methylation. These marks are not only indicative of a given cell state; they are also functionally important during reprogramming. In this chapter I will review our current understanding of the mechanism of reprogramming and the role chromatin marks and the associated chromatin-modifier proteins play in this process.
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    Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity
    (Cell Press, 2014) Das, Partha Pratim; Shao, Zhen; Beyaz, Semir; Apostolou, Eftychia; Pinello, Luca; De Los Angeles, Alejandro; O'Brien, Kassandra; Atsma, Jennifer Marino; Fujiwara, Yuko; Minh Nguyen; Ljuboja, Damir; Guo, Guoji; Woo, Andrew; Yuan, Guo-Cheng; Daley, George; Hochedlinger, Konrad; Kim, Jonghwan; Orkin, Stuart H.; N/A; Önder, Tamer Tevfik; Faculty Member; School of Medicine; 42946
    Self-renewal and pluripotency of embryonic stem cells (ESCs) are established by multiple regulatory pathways operating at several levels. The roles of histone demethylases (HDMs) in these programs are incompletely defined. We conducted a functional RNAi screen for HDMs and identified five potential HDMs essential for mouse ESC identity. In-depth analyses demonstrate that the closely related HDMs Jmjd2b and Jmjd2c are necessary for self-renewal of ESCs and induced pluripotent stem cell generation. Genome-wide occupancy studies reveal that Jmjd2b unique, Jmjd2c unique, and Jmjd2b-Jmjd2c common target sites belong to functionally separable Core, Polycomb repressive complex (PRC), and Myc regulatory modules, respectively. Jmjd2b and Nanog act through an interconnected regulatory loop, whereas Jmjd2c assists PRC2 in transcriptional repression. Thus, two HDMs of the same subclass exhibit distinct and combinatorial functions in control of the ESC state. Such complexity of HDM function reveals an aspect of multilayered transcriptional control.
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    Publication
    New lessons learned from disease modeling with induced pluripotent stem cells
    (Elsevier, 2012) Daley, George Q.; N/A; Önder, Tamer Tevfik; Faculty Member; School of Medicine; 42946
    Cellular reprogramming and generation of induced pluripotent stem cells (iPSCs) from adult cell types have enabled the creation of patient-specific stem cells for use in disease modeling. To date, many iPSC lines have been generated from a variety of disorders, which have then been differentiated into disease-relevant cell types. When a disease-specific phenotype is detectable in such differentiated cells, the reprogramming technology provides a new opportunity to identify aberrant disease-associated pathways and drugs that can block them. Here, we highlight recent progress as well as limitations in the use of iPSCs to recapitulate disease phenotypes and to screen for therapeutics in vitro.
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    Systems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast cancer
    (American Society Biochemistry Molecular Biology, 2019) Saatci, Ozge; Ersan, Pelin Gulizar; Trappe, Kathrin; Renard, Bernhard Y.; Tuncbag, Nurcan; Sahin, Ozgur; Department of Molecular Biology and Genetics; N/A; N/A; Department of Molecular Biology and Genetics; Önder, Tamer Tevfik; Kagiali, Zeynep Cansu Üretmen; Şanal, Erdem; Karayel, Özge; Köken, Ayşe Nur Polat; Sıcakkan, Nurhan Özlü; Faculty Member; Faculty Member; PhD Student; PhD Student; Master Student; Master Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Sciences; School of Medicine; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; 105301; 42946; N/A; N/A; N/A; N/A
    Epithelial-mesenchymal transition (EMT) is driven by complex signaling events that induce dramatic biochemical and morphological changes whereby epithelial cells are converted into cancer cells. However, the underlying molecular mechanisms remain elusive. Here, we used mass spectrometry based quantitative proteomics approach to systematically analyze the post-translational biochemical changes that drive differentiation of human mammary epithelial (HMLE) cells into mesenchymal. We identified 314 proteins out of more than 6,000 unique proteins and 871 phosphopeptides out of more than 7,000 unique phosphopeptides as differentially regulated. We found that phosphoproteome is more unstable and prone to changes during EMT compared with the proteome and multiple alterations at proteome level are not thoroughly represented by transcriptional data highlighting the necessity of proteome level analysis. We discovered cell state specific signaling pathways, such as Hippo, sphingolipid signaling, and unfolded protein response (UPR) by modeling the networks of regulated proteins and potential kinase-substrate groups. We identified two novel factors for EMT whose expression increased on EMT induction: DnaJ heat shock protein family (Hsp40) member B4 (DNAJB4) and cluster of differentiation 81 (CD81). Suppression of DNAJB4 or CD81 in mesenchymal breast cancer cells resulted in decreased cell migration in vitro and led to reduced primary tumor growth, extravasation, and lung metastasis in vivo. Overall, we performed the global proteomic and phosphoproteomic analyses of EMT, identified and validated new mRNA and/ or protein level modulators of EMT. This work also provides a unique platform and resource for future studies focusing on metastasis and drug resistance.
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    Loss of PRC2 or KMT2D-COMPASS generates two quasi-mesenchymal cell states with distinct metastatic abilities
    (American Association for Cancer Research (AACR), 2020) Zhang, Yun; Donaher, Joana Liu; Das, Sunny; Li, Xin; Reinhardt, Ferenc; Krall, Jordan A.; Lambert, Arthur W.; Thiru, Prathapan; Keys, Heather R.; Khan, Mehreen; Hofree, Matan; Wilson, Molly M.; Tyler, Michael; Tirosh, Itay; Regev, Aviv; Lees, Jacqueline; Weinberg, Robert A.; Bayram, Özlem Yedier; Lack, Nathan Alan; Önder, Tamer Tevfik; Önder, Tuğba Bağcı; Researcher; Faculty Member; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; N/A; N/A; School of Medicine; School of Medicine; School of Medicine; N/A; 120842; 42946; 184359
    The epithelial-mesenchymal transition (EMT) is a key cell-biological program enabling carcinoma cell phenotypic plasticity. Accumulating evidence suggests EMT programs do not operate as a stereotypical program that functions as a binary switch, shifting cells from an epithelial (E) to a mesenchymal (M) state. Instead, EMT programs generate cells that enter into a series of intermediate states arrayed along the E-M phenotypic spectrum. At present, we still lack a coherent understanding of how carcinoma cells control their entrance into and residence in these various intermediate states, and which EMT intermediate state(s) favour the metastatic process. Here we characterize a new level of regulation of EMT, consisting of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, that function as critical regulators to maintain stable residence of both normal and neoplastic cells in an epithelial state via regulating the downstream response of EMT-inducing signals. Dysfunction of either of these two complexes causes cells that were previously stably ensconced in an epithelial state to lapse into two distinct quasi-mesenchymal cell states with strongly differing metastatic abilities. These observations uncover a novel mechanism that regulates E-M plasticity, specifies which intermediate EMT state a cell will reside in, and thereby determines the metastatic ability of carcinoma cells.
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    hCG ımproves luteal function and promotes progesterone output through the activation of JNK pathway in the luteal granulosa cells of the stimulated IVF cycles
    (Oxford Univ Press Inc, 2020) N/A; Bildik, Gamze; Akın, Nazlı; Esmaeilian, Yashar; Hela, Francesko; Yakın, Kayhan; Önder, Tamer Tevfik; Urman, Cumhur Bülent; Öktem, Özgür; Teaching Faculty; Master Student; Researcher; PhD Student; Faculty Member; Faculty Member; Faculty Member; Faculty Member; School of Medicine; Graduate School of Health Sciences; N/A; Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 106822; 42946; 12147; 102627
    Human chorionic gonadotropin (hCG) is a luteotropic hormone that promotes the survival and steroidogenic activity of corpus luteum (CL) by acting through luteinizing hormone receptors (LHRs) expressed on luteinized theca and granulosa cells (GCs). Therefore, it is used to support luteal phase in in vitro fertilization (IVF) cycles to improve clinical pregnancy rates and prevent miscarriage. However, the molecular mechanism underlying this action of hCG is not well characterized. To address this question, we designed an in vitro translational research study on the luteal GCs obtained from 58 IVF patients. hCG treatment at different concentrations and time points activated c-Jun N-terminal kinase (JNK) pathway and significantly increased its endogenous kinase activity along with upregulated expression of steroidogenic enzymes (steroidogenic acute regulatory protein (stAR), 3β-Hydroxysteroid dehydrogenase (3β-HSD)) in a dose-dependent manner in the luteal GCs. As a result, in vitro P production of the cells was significantly enhanced after hCG. When JNK pathway was inhibited pharmacologically or knocked-down with small interfering RNA luteal function was compromised, P4 production was declined along with the expression of stAR and 3β-HSD in the cells. Further, hCG treatment after JNK inhibition failed to correct the luteal defect and promote P4 output. Similar to hCG, luteinizing hormone (LH) treatment improved luteal function as well and this action of LH was associated with JNK activation in the luteal GCs. These findings could be important from the perspective of CL biology and luteal phase in human because we for the first time identify a critical role for JNK signaling pathway downstream LHR activation by hCG/LH in luteal GCs.
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    Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis
    (Nature Portfolio, 2022) Zhang, Yun; Donaher, Joana Liu; Das, Sunny; Li, Xin; Reinhardt, Ferenc; Krall, Jordan A.; Lambert, Arthur W.; Thiru, Prathapan; Keys, Heather R.; Khan, Mehreen; Hofree, Matan; Wilson, Molly M.; Tyler, Michael; Tirosh, Itay; Regev, Aviv; Lees, Jacqueline A.; Weinberg, Robert A.; N/A; Lack, Nathan Alan; Bayram, Özlem Yedier; Önder, Tamer Tevfik; Önder, Tuğba Bağcı; Faculty Member; Researcher; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; 120842; N/A; 42946; 184359
    Through genome-wide and focused CRISPR screens, Zhang et al. discover that loss of PRC2 or KMT2D-COMPASS enables distinct EMT trajectories, which exert differential effects on the metastatic capability of carcinoma cells. Epithelial-mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E-M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance into and continued residence in these various states, and which of these states favour the process of metastasis. Here we characterize a layer of EMT-regulating machinery that governs E-M plasticity (EMP). This machinery consists of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, which operate as critical regulators to maintain a stable epithelial state. Interestingly, loss of these two complexes unlocks two distinct EMT trajectories. Dysfunction of PRC2, but not KMT2D-COMPASS, yields a quasi-mesenchymal state that is associated with highly metastatic capabilities and poor survival of patients with breast cancer, suggesting that great caution should be applied when PRC2 inhibitors are evaluated clinically in certain patient cohorts. These observations identify epigenetic factors that regulate EMP, determine specific intermediate EMT states and, as a direct consequence, govern the metastatic ability of carcinoma cells.