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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3
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Item Metadata only In skeletal muscle and neural crest cells, SMCHD1 regulates biological pathways relevant for Bosma syndrome and facioscapulohumeral dystrophy phenotype(Oxford Univ Press, 2023) 0000-0002-4070-7997; Laberthonniere, Camille; Delourme, Megane; Chevalier, Raphael; Dion, Camille; Ganne, Benjamin; Hirst, David; Caron, Leslie; Perrin, Pierre; Adelaide, Jose; Chaffanet, Max; Xue, Shifeng; Nguyen, Karine; Reversade, Bruno; Dejardin, Jerome; Baudot, Anais; Robin, Jerome D.; Magdinier, Frederique; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked to mutations in SMCHD1 that encodes the structural maintenance of chromosomes flexible hinge domain containing 1 chromatin-associated factor. In humans, its function as well as the impact of its mutations remains poorly defined. To fill this gap, we determined the episignature associated with heterozygous SMCHD1 variants in primary cells and cell lineages derived from induced pluripotent stem cells for Bosma arhinia and microphthalmia syndrome (BAMS) and type 2 facioscapulohumeral dystrophy (FSHD2). In human tissues, SMCHD1 regulates the distribution of methylated CpGs, H3K27 trimethylation and CTCF at repressed chromatin but also at euchromatin. Based on the exploration of tissues affected either in FSHD or in BAMS, i.e. skeletal muscle fibers and neural crest stem cells, respectively, our results emphasize multiple functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable targets or phenotypical outcomes. We concluded that in rare genetic diseases, SMCHD1 variants impact gene expression in two ways: (i) by changing the chromatin context at a number of euchromatin loci or (ii) by directly regulating some loci encoding master transcription factors required for cell fate determination and tissue differentiation.Item Metadata only Behçet's disease: a comprehensive review on the role of HLA-B*51, antigen presentation, and inflammatory cascade(MDPI, 2023) 0000-0002-0866-865X; 0000-0001-6561-196X; 0000-0003-3222-874X; 0000-0002-9923-205X; N/A; N/A; N/A; N/A; Khoshbakht, Saba; Vural, Seçil; Vural, Atay; Başkurt, Defne; PhD Student; Faculty Member; Faculty Member; Undergraduate Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; N/A; 189340; 182369; N/ABehcet's disease (BD) is a complex, recurring inflammatory disorder with autoinflammatory and autoimmune components. This comprehensive review aims to explore BD's pathogenesis, focusing on established genetic factors. Studies reveal that HLA-B*51 is the primary genetic risk factor, but non-HLA genes (ERAP1, IL-10, IL23R/IL-12RB2), as well as innate immunity genes (FUT2, MICA, TLRs), also contribute. Genome-wide studies emphasize the significance of ERAP1 and HLA-I epistasis. These variants influence antigen presentation, enzymatic activity, and HLA-I peptidomes, potentially leading to distinct autoimmune responses. We conducted a systematic review of the literature to identify studies exploring the association between HLA-B*51 and BD and further highlighted the roles of innate and adaptive immunity in BD. Dysregulations in Th1/Th2 and Th17/Th1 ratios, heightened clonal cytotoxic (CD8+) T cells, and reduced T regulatory cells characterize BD's complex immune responses. Various immune cell types (neutrophils, gamma delta T cells, natural killer cells) further contribute by releasing cytokines (IL-17, IL-8, GM-CSF) that enhance neutrophil activation and mediate interactions between innate and adaptive immunity. In summary, this review advances our understanding of BD pathogenesis while acknowledging the research limitations. Further exploration of genetic interactions, immune dysregulation, and immune cell roles is crucial. Future studies may unveil novel diagnostic and therapeutic strategies, offering improved management for this complex disease.Item Metadata only The signalling lipid PI3,5P 2 is essential for timely mitotic exit(Royal Society Publishing, 2023) 0000-0003-2570-1367; N/A; N/A; 0000-0002-3470-7421; Department of Molecular Biology and Genetics; N/A; N/A; N/A; Çaydaşı, Ayşe Koca; Bektaş, Şeyma Nur; Bekdaş, Barış; Huda, Mariam; Faculty Member; PhD Student; Master Student; PhD Student; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; 252978; N/A; N/A; N/ACoordination of mitotic exit with chromosome segregation is key for successful mitosis. Mitotic exit in budding yeast is executed by the mitotic exit network (MEN), which is negatively regulated by the spindle position checkpoint (SPOC). SPOC kinase Kin4 is crucial for SPOC activation in response to spindle positioning defects. Here, we report that the lysosomal signalling lipid phosphatidylinositol-3,5-bisphosphate (PI3,5P 2) has an unanticipated role in the timely execution of mitotic exit. We show that the lack of PI3,5P 2 causes a delay in mitotic exit, whereas elevated levels of PI3,5P 2 accelerates mitotic exit in mitotic exit defective cells. Our data indicate that PI3,5P 2 promotes mitotic exit in part through impairment of Kin4. This process is largely dependent on the known PI3,5P 2 effector protein Atg18. Our work thus uncovers a novel link between PI3,5P 2 and mitotic exit. © 2023 Royal Society Publishing. All rights reserved.Item Metadata only Exosome-loaded microneedle patches: Promising factor delivery route(Elsevier, 2023) 0000-0003-2945-018X; Fathi-Karkan, Sonia; Narmi, Maryam Taghavi; Mardi, Narges; Amini, Hassan; Saghati, Sepideh; Abrbekoh, Fateme Nazary; Saghebasl, Solmaz; Rahbarghazi, Reza; Khoshfetrat, Ali Baradari; N/A; Heidarzadeh, Morteza; PhD Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health SciencesDuring the past decades, the advent of different microneedle patch (MNPs) systems paves the way for the targeted and efficient delivery of several growth factors into the injured sites. MNPs consist of several micro-sized (25-1500 & mu;m) needle rows for painless delivery of incorporated therapeutics and increase of regenerative outcomes. Recent data have indicated the multifunctional potential of varied MNP types for clinical applications. Advances in the application of materials and fabrication processes enable researchers and clinicians to apply several MNP types for different purposes such as inflammatory conditions, ischemic disease, metabolic disorders, vaccination, etc. Exosomes (Exos) are one of the most interesting biological bioshuttles that participate in cell-tocell paracrine interaction with the transfer of signaling biomolecules. These nano-sized particles, ranging from 50 to 150 nm, can exploit several mechanisms to enter the target cells and deliver their cargo into the cytosol. In recent years, both intact and engineered Exos have been increasingly used to accelerate the healing process and restore the function of injured organs. Considering the numerous benefits provided by MNPs, it is logical to hypothesize that the development of MNPs loaded with Exos provides an efficient therapeutic platform for the alleviation of several pathologies. In this review article, the authors collected recent advances in the application of MNP-loaded Exos for therapeutic purposes.Publication Metadata only 3D printed styrax liquidus (liquidambar orientalis miller)-loaded poly (l-lactic acid)/chitosan based wound dressing material: fabrication, characterization, and biocompatibility results(Elsevier, 2023) Cakmak, Hanife Yuksel; Ege, Hasan; Yilmaz, Senanur; Agturk, Gokhan; Enguven, Gozde; Sarmis, Abdurrahman; Cakmak, Zeren; Gunduz, Oguzhan; Ege, Zeynep Ruya; Yöntem, Fulya Dal; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of MedicineThe medicinal plant of Styrax liquidus (ST) (sweet gum balsam) which extracted from Liquidambar orientalis Mill tree, was loaded into the 3D printed polylactic acid (PLA)/chitosan (CS) based 3D printed scaffolds to investigate its wound healing and closure effect, in this study. The morphological and chemical properties of the ST loaded 3D printed scaffolds with different concentrations (1 %, 2 %, and 3 % wt) were investigated by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FT-IR), respectively. In addition, the me-chanical and thermal properties of the materials were investigated by Tensile test and Differential Scanning Calorimetry (DSC), respectively. The antimicrobial activities of the ST loaded 3D printed scaffolds and their incubation media in the PBS (pH 7.4, at 37 degrees C for 24 h) were investigated on two Gram-positive and two Gram -negative standard pathogenic bacteria with the agar disc diffusion method. The colorimetric MTT assay was used to determine the cell viability of human fibroblast cells (CCD-1072Sk) incubated with free ST, ST loaded, and unloaded 3D printed scaffolds. The 1 % and 2 % (wt) ST loaded PLA/CS/ST 3D printed scaffolds showed an increase in the cell number. Annexin V/PI double stain assay was performed to test whether early or late apoptosis was induced in the PLA/CS/1 % ST and PLA/CS/2 % ST loaded groups and the results were consistent with the MTT assay. Furthermore, a wound healing assay was carried out to investigate the effect of ST loaded 3D printed scaffolds on wound healing in CCD-1072Sk cells. The highest wound closure compared to the control group was observed on cells treated with PLA/CS/1 % ST for 72 h. According to the results, novel biocompatible ST loaded 3D printed scaffolds with antimicrobial effect can be used as wound healing material for potential tissue engineering applications.Publication Metadata only Author correction: combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma(Nature Research, 2024) Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noël PB, Braren R, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Heßmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT.; Koç University HospitalIn the originally published version of this article, there were errors in the histological sections depicted in Supplementary Figs. 4 and 10. Specifically: In Supplementary Fig. 4, the image of the Ki67 immunohistochemistry (IHC) for the Gemcitabine+JQ1 group was incorrect In Supplementary Fig. 10, the pSTAT3 image for the IHC for the JQ1 group was incorrect In Supplementary Fig. 10, Ki67 and MYC IHC images for JQ1 and JQ1+SAHA were swapped In Supplementary Fig. 4, the image of the Ki67 immunohistochemistry (IHC) for the Gemcitabine+JQ1 group was incorrect In Supplementary Fig. 10, the pSTAT3 image for the IHC for the JQ1 group was incorrect In Supplementary Fig. 10, Ki67 and MYC IHC images for JQ1 and JQ1+SAHA were swapped The original data were available and these errors have been corrected in the Supplementary Information accompanying this notice. Additionally, the authors wish to clarify that the Sirius Red staining for the control and JQ1 groups were identical in both Supplementary Figs. 4 and 10 because the control mice (JQ1 only or control treatment) were shared between experiments. To avoid confusion, the sections depicting Sirius Red staining for the control and JQ1 groups in Supplementary Fig. 4 were replaced with alternative sections from the same respective samplesPublication Metadata only Shared proteins and pathways of cardiovascular and cognitive diseases: relation to vascular cognitive impairment(Amer Chemical Soc, 2024) Picon-Pages, Pol; Garcia-Elias, Anna; Tajes, Marta; Munoz, Francisco J.; Oliva, Baldomero; Garcia-Ojalvo, Jordi; Barbu, Eduard; Vicente, Raul; Nattel, Stanley; Ois, Angel; Puig-Pijoan, Albert; Department of Chemical and Biological Engineering;Department of Computer Engineering; Zeylan, Melisa Ece; Şenyüz, Simge; Keskin, Özlem; Gürsoy, Attila; Graduate School of Sciences and Engineering; College of EngineeringOne of the primary goals of systems medicine is the detection of putative proteins and pathways involved in disease progression and pathological phenotypes. Vascular cognitive impairment (VCI) is a heterogeneous condition manifesting as cognitive impairment resulting from vascular factors. The precise mechanisms underlying this relationship remain unclear, which poses challenges for experimental research. Here, we applied computational approaches like systems biology to unveil and select relevant proteins and pathways related to VCI by studying the crosstalk between cardiovascular and cognitive diseases. In addition, we specifically included signals related to oxidative stress, a common etiologic factor tightly linked to aging, a major determinant of VCI. Our results show that pathways associated with oxidative stress are quite relevant, as most of the prioritized vascular cognitive genes and proteins were enriched in these pathways. Our analysis provided a short list of proteins that could be contributing to VCI: DOLK, TSC1, ATP1A1, MAPK14, YWHAZ, CREB3, HSPB1, PRDX6, and LMNA. Moreover, our experimental results suggest a high implication of glycative stress, generating oxidative processes and post-translational protein modifications through advanced glycation end-products (AGEs). We propose that these products interact with their specific receptors (RAGE) and Notch signaling to contribute to the etiology of VCI.Publication Metadata only Navigating centriolar satellites: the role of PCM1 in cellular and organismal processes(WILEY, 2024) Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Begar, Efe; Seyrek, Ece; Karalar, Elif Nur Fırat; Graduate School of Sciences and Engineering; College of SciencesCentriolar satellites are ubiquitous membrane-less organelles that play critical roles in numerous cellular and organismal processes. They were initially discovered through electron microscopy as cytoplasmic granules surrounding centrosomes in vertebrate cells. These structures remained enigmatic until the identification of pericentriolar material 1 protein (PCM1) as their molecular marker, which has enabled their in-depth characterization. Recently, centriolar satellites have come into the spotlight due to their links to developmental and neurodegenerative disorders. This review presents a comprehensive summary of the major advances in centriolar satellite biology, with a focus on studies that investigated their biology associated with the essential scaffolding protein PCM1. We begin by exploring the molecular, cellular, and biochemical properties of centriolar satellites, laying the groundwork for a deeper understanding of their functions and mechanisms at both cellular and organismal levels. We then examine the implications of their dysregulation in various diseases, particularly highlighting their emerging roles in neurodegenerative and developmental disorders, as revealed by organismal models of PCM1. We conclude by discussing the current state of knowledge and posing questions about the adaptable nature of these organelles, thereby setting the stage for future research.Publication Metadata only SETD3 regulates endoderm differentiation of mouse embryonic stem cells through canonical Wnt signaling pathway(Wiley, 2024) Alganatay, Ceren; Balbasi, Emre; Sezginmert, Dersu; Cizmecioglu, Nihal Terzi; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Tunçbağ, Nurcan; College of EngineeringWith self-renewal and pluripotency features, embryonic stem cells (ESCs) provide an invaluable tool to investigate early cell fate decisions. Pluripotency exit and lineage commitment depend on precise regulation of gene expression that requires coordination between transcription (TF) and chromatin factors in response to various signaling pathways. SET domain-containing 3 (SETD3 Delta) is a methyltransferase that can modify histones in the nucleus and actin in the cytoplasm. Through an shRNA screen, we previously identified SETD3 as an important factor in the meso/endodermal lineage commitment of mouse ESCs (mESC). In this study, we identified SETD3-dependent transcriptomic changes during endoderm differentiation of mESCs using time-course RNA-seq analysis. We found that SETD3 is involved in the timely activation of the endoderm-related gene network. The canonical Wnt signaling pathway was one of the markedly altered signaling pathways in the absence of SETD3. The assessment of Wnt transcriptional activity revealed a significant reduction in Setd3-deleted (setd3 increment ) mESCs coincident with a decrease in the nuclear pool of the key TF beta-catenin level, though no change was observed in its mRNA or total protein level. Furthermore, a proximity ligation assay (PLA) found an interaction between SETD3 and beta-catenin. We were able to rescue the differentiation defect by stably re-expressing SETD3 or activating the canonical Wnt signaling pathway by changing mESC culture conditions. Our results suggest that alterations in the canonical Wnt pathway activity and subcellular localization of beta-catenin might contribute to the endoderm differentiation defect of setd3 Delta increment mESCs.Publication Metadata only A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta(Oxford Univ Press, 2019) Guillemyn, Brecht; Demuynck, Lynn; Sips, Patrick; De Paepe, Anne; Syx, Delfien; Coucke, Paul J.; Malfait, Fransiska; Symoens, Sofie; N/A; Kayserili, Hülya; Faculty Member; School of Medicine; 7945The cyclic adenosine monophosphate responsive element binding protein 3-like 1 (CREB3L1) gene codes for the endoplasmic reticulum stress transducer old astrocyte specifically induced substance (OASIS), which has an important role in osteoblast differentiation during bone development. Deficiency of OASIS is linked to a severe form of autosomal recessive osteogenesis imperfecta (OI), but only few patients have been reported. We identified the first homozygous pathogenic missense variant [p.(Ala304Val)] in a patient with lethal OI, which is located within the highly conserved basic leucine zipper domain, four amino acids upstream of the DNA binding domain. In vitro structural modeling and luciferase assays demonstrate that this missense variant affects a critical residue in this functional domain, thereby decreasing the type I collagen transcriptional binding ability. In addition, overexpression of the mutant OASIS protein leads to decreased transcription of the SEC23A and SEC24D genes, which code for components of the coat protein complex type II (COPII), and aberrant OASIS signaling also results in decreased protein levels of SEC24D. Our findings therefore provide additional proof of the potential involvement of the COPII secretory complex in the context of bone-associated disease.