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Publication Open Access AKT signaling modifies the balance between cell proliferation and migration in neural crest cells from patients affected with Bosma Arhinia and Microphthalmia Syndrome(Multidisciplinary Digital Publishing Institute (MDPI), 2021) Laberthonnière, C.; Novoa-Del-Toro, E. M.; Chevalier, R.; Broucqsault, N.; Rao, V. V.; Trani, J. P.; Nguyen, K.; Xue, S.; Robin, J. D.; Baudot, A.; Magdinier, F.; Reversade, Bruno; Faculty Member; School of MedicineOver the recent years, the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain Containing 1) chromatin-associated factor has triggered increasing interest after the identification of variants in three rare and unrelated diseases, type 2 Facio Scapulo Humeral Dystrophy (FSHD2), Bosma Arhinia and Microphthalmia Syndrome (BAMS), and the more recently isolated hypogonadotrophic hypogonadism (IHH) combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD). However, it remains unclear why certain mutations lead to a specific muscle defect in FSHD while other are associated with severe congenital anomalies. To gain further insights into the specificity of SMCHD1 variants and identify pathways associated with the BAMS phenotype and related neural crest defects, we derived induced pluripotent stem cells from patients carrying a mutation in this gene. We differentiated these cells in neural crest stem cells and analyzed their transcriptome by RNA-Seq. Besides classical differential expression analyses, we analyzed our data using MOGAMUN, an algorithm allowing the extraction of active modules by integrating differential expression data with biological networks. We found that in BAMS neural crest cells, all subnetworks that are associated with differentially expressed genes converge toward a predominant role for AKT signaling in the control of the cell proliferation-migration balance. Our findings provide further insights into the distinct mechanism by which defects in neural crest migration might contribute to the craniofacial anomalies in BAMS.Publication Open Access Bosonic helium droplets with cationic impurities: onset of electrostriction and snowball effects from quantum calculations(American Institute of Physics (AIP) Publishing, 2007) Coccia, E.; Bodo, E.; Marinetti, F.; Gianturco, F. A.; Yıldırım, E.; Yurtsever, M.; Department of Chemistry; Department of Chemistry; Yurtsever, İsmail Ersin; Faculty Member; College of Sciences; 7129Variational Monte Carlo and diffusion Monte Carlo calculations have been carried out for cations such as Li(+), Na(+), and K(+) as dopants of small helium clusters over a range of cluster sizes up to about 12 solvent atoms. The interaction has been modeled through a sum-of-potential picture that disregards higher order effects beyond atom-atom and atom-ion contributions. The latter were obtained from highly correlated ab initio calculations over a broad range of interatomic distances. This study focuses on two of the most striking features of the microsolvation in a quantum solvent of a cationic dopant: electrostriction and snowball effects. They are discussed here in detail and in relation with the nanoscopic properties of the interaction forces at play within a fully quantum picture of the cluster features.Publication Open Access Characterization of the conformational state and flexibility of HIV-1 glycoprotein gp120 core domain(American Society for Biochemistry and Molecular Biology (ASBMB), 2004) Pan, Yongping.; Ma, Buyong; Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Keskin, Özlem; Faculty Member; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; 26605gp120 is key to the human immunodeficiency virus type 1 viral cell entry. Knowledge of the detailed conformational states of gp120 is crucial to intervention, yet the unbound form is still resistant to structural characterization probably because of its flexibility. Toward this goal, we performed molecular dynamics simulations on the wild type gp120 core domain extracted from its ternary crystal structure and on a modeled mutant, S375W, that experimentally has a significantly different phenotype from the wild type. Although the mutant retained a bound-like conformation, the wild type drifted to a different conformational state. The wild type beta strands 2 and 3 of the bridging sheet were very mobile and partially unfolded, and the organization among the inner and outer domains and beta strands 20 and 21 of the bridging sheet, near the mutation site, was more open than in the bound form, although the overall structure was maintained. These differences were apparently a result of the strengthening of the hydrophobic core in the mutant. This stabilization further explains the experimentally significantly different thermodynamic properties between the wild type and the mutant. Taken together, our results suggest that the free form, although different from the bound state, shares many of the bound structural features. The observed loss of freedom near the binding site, rather than the previously hypothesized more dramatic conformational transition from the unbound to the bound state, appears to be the major contributor to the large entropy cost for the CD4 binding to the wild type.Publication Open Access CRY1-CBS binding regulates circadian clock function and metabolism(Wiley, 2021) Growe, Jacqueline; Selby, Christopher P.; Rhoades, Seth D.; Malik, Dania; Francey, Lauren J.; Sancar, Aziz; Kruger, Warren D.; Hogenesch, John B.; Weljie, Aalim; Anafi, Ron C.; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; N/A; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Kayıtmazbatır, Sibel Çal; Öner, Haşimcan; Asımgil, Hande; Kavaklı, İbrahim Halil; PhD Student; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; N/A; N/A; 40319Circadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here, we report that cystathionine beta-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein cryptochrome 1 (CRY1). In cells, CBS augments CRY1-mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic Cbs(Zn/Zn) mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1(-/-) mice show reduced CBS activity that normalizes after the addition of exogenous wild-type (WT) CRY1. Metabolomic analysis of WT, Cbs(Zn/Zn), Cry1(-/-), and Cry2(-/-) samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1-induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control.Publication Open Access DNA repair by photolyases(Elsevier, 2019) Öztürk, Nuri; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Kavaklı, İbrahim Halil; Gül, Şeref; Faculty Member; College of Sciences; Graduate School of Sciences and Engineering; 40319; N/APhotolyases belong to the cryptochrome/photolyase protein family (CPF) which perform different functions such as DNA repair, circadian photoreceptor, and transcriptional regulation. Photolyase is a flavoprotein that repairs UV-induced DNA damages of cyclobutane pyrimidine dimer (CPD) and pyrimidine-pyrimidone (6-4) photoproducts using blue-light as an energy source. This enzyme has two chromophores: flavin adenine dinucleotide (FAD) as a cofactor and a photoantenna such as methenyltetrahydrofolate (MTHF). The FAD is essential for catalysis of the DNA repair. The second chromophore absorbs photons from the blue light spectrum and transfers energy to FAD to increase the repair efficiency of the enzyme. Phylogenetic analysis in which amino acid sequences of several hundreds of CPF members are used suggests that they form more classes than we have considered so far. In this chapter, we discussed structure-functions and reaction mechanisms of different classes of photolyases.Publication Open Access ENKD1 is a centrosomal and ciliary microtubule-associated protein important for primary cilium content regulation(Wiley, 2022) Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Tiryaki, Fatmanur; Deretic, Jovana; Karalar, Elif Nur Fırat; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 206349Centrioles and cilia are conserved, microtubule-based structures critical for cell function and development. Their dysfunction causes cancer and developmental disorders. How microtubules are organized into ordered structures by microtubule-associated proteins (MAPs) and tubulin modifications is best understood during mitosis but is largely unexplored for the centrioles and the ciliary axoneme, which are composed of stable microtubules that maintain their length at a steady-state. In particular, we know little about the identity of the centriolar and ciliary MAPs and how they work together during the assembly and maintenance of the cilium and centriole. Here, we identified the Enkurin domain containing 1 (ENKD1) as a component of the centriole wall and the axoneme in mammalian cells and showed that it has extensive proximity interactions with these compartments and MAPs. Using in vitro and cellular assays, we found that ENKD1 is a new MAP that regulates microtubule organization and stability. Consistently, we observed an increase in tubulin polymerization and microtubule stability, as well as disrupted microtubule organization in ENKD1 overexpression. Cells depleted for ENKD1 were defective in ciliary length and content regulation and failed to respond to Hedgehog pathway activation. Together, our results advance our understanding of the functional and regulatory relationship between MAPs and the primary cilium.Publication Open Access Epitranscriptomics of ischemic heart disease-the IHD-EPITRAN study design and objectives(Multidisciplinary Digital Publishing Institute (MDPI), 2021) Sikorski, Vilbert; Karjalainen, Pasi; Blokhina, Daria; Oksaharju, Kati; Khan, Jahangir; Katayama, Shintaro; Rajala, Helena; Suihko, Satu; Tuohinen, Suvi; Teittinen, Kari; Nummi, Annu; Nykanen, Antti; Eskin, Arda; Stark, Christoffer; Biancari, Fausto; Kiss, Jan; Simpanen, Jarmo; Ropponen, Jussi; Lemstrom, Karl; Savinainen, Kimmo; Lalowski, Maciej; Kaarne, Markku; Jormalainen, Mikko; Elomaa, Outi; Koivisto, Pertti; Raivio, Peter; Backstrom, Pia; Dahlbacka, Sebastian; Syrjala, Simo; Vainikka, Tiina; Vahasilta, Tiina; Karelson, Mati; Mervaala, Eero; Juvonen, Tatu; Laine, Mika; Laurikka, Jari; Vento, Antti; Kankuri, Esko; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Tunçbağ, Nurcan; Faculty Member; School of Medicine; College of Engineering; 245513Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m(6)A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m(6)A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m(6)A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.Publication Open Access Exosomal delivery of therapeutic modulators through the blood-brain barrier; promise and pitfalls(BioMed Central, 2021) Eslami Abriz, Aysan; Zarebkohan, Amir; Rahbarghazi, Reza; Özdemir, Yasemin Gürsoy; Kaya, Mehmet; Sokullu, Emel; Heidarzadeh, Morteza; Faculty Member; Faculty Member; PhD Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences; 170592; 10486; 163024; N/ANowadays, a large population around the world, especially the elderly, suffers from neurological inflammatory and degenerative disorders/diseases. Current drug delivery strategies are facing different challenges because of the presence of the BBB, which limits the transport of various substances and cells to brain parenchyma. Additionally, the low rate of successful cell transplantation to the brain injury sites leads to efforts to find alternative therapies. Stem cell byproducts such as exosomes are touted as natural nano-drug carriers with 50-100 nm in diameter. These nano-sized particles could harbor and transfer a plethora of therapeutic agents and biological cargos to the brain. These nanoparticles would offer a solution to maintain paracrine cell-to-cell communications under healthy and inflammatory conditions. The main question is that the existence of the intact BBB could limit exosomal trafficking. Does BBB possess some molecular mechanisms that facilitate the exosomal delivery compared to the circulating cell? Although preliminary studies have shown that exosomes could cross the BBB, the exact molecular mechanism(s) beyond this phenomenon remains unclear. In this review, we tried to compile some facts about exosome delivery through the BBB and propose some mechanisms that regulate exosomal cross in pathological and physiological conditions.Publication Open Access Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential(Nature Portfolio, 2022) Kneppers, J.; Severson, T.M.; Siefert, J.C.; Schol, P.; Joosten, S.E.P.; Yu, I.P.L.; Huang, C.F.; Morova, T.; Giambartolomei, C.; Seo, J.H.; Baca, S.C.; Carneiro, I.; Emberly, E.; Pasaniuc, B.; Jerónimo, C.; Henrique, R.; Freedman, M.L.; Wessels, L.F.A.; Bergman, A.M.; Zwart, W.; N/A; Lack, Nathan Alan; Altıntaş, Umut Berkay; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Sciences and Engineering; 120842; N/AAndrogen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.Publication Open Access IDH mutations in glioma: double-edged sword in clinical applications?(Multidisciplinary Digital Publishing Institute (MDPI), 2021) Kayabölen, Alişan; Yılmaz, Ebru; Önder, Tuğba Bağcı; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of Medicine; N/A; N/A; 184359Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (alpha-KG), an intermediate in the citric acid cycle. Specific mutations in the genes encoding IDHs cause neomorphic enzymatic activity that produces D-2-hydroxyglutarate (2-HG) and result in the inhibition of alpha-KG-dependent enzymes such as histone and DNA demethylases. Thus, chromatin structure and gene expression profiles in IDH-mutant gliomas appear to be different from those in IDH-wildtype gliomas. IDH mutations are highly common in lower grade gliomas (LGG) and secondary glioblastomas, and they are among the earliest genetic events driving tumorigenesis. Therefore, inhibition of mutant IDH enzymes in LGGs is widely accepted as an attractive therapeutic strategy. On the other hand, the metabolic consequences derived from IDH mutations lead to selective vulnerabilities within tumor cells, making them more sensitive to several therapeutic interventions. Therefore, instead of shutting down mutant IDH enzymes, exploiting the selective vulnerabilities caused by them might be another attractive and promising strategy. Here, we review therapeutic options and summarize current preclinical and clinical studies on IDH-mutant gliomas.