Yavuz Oktay Laboratory

LOGOküçük

Oktay Lab iBG yavuz.oktay at deu.edu.tr
Members
Burcu Ekinci (PhD Student)
Fadime Öztoprak (PhD Student)
Elmasnur Yılmaz (MSc Student)
Tutku Yaraş (MSc Student)
Ece Sönmezler (MSc Student)
Ebru Diler (MSc Student)

 

OVERVIEW

Next generation sequencing (NGS) technologies have revolutionized our approach to studying the genetic basis of diseases and caused a paradigm shift in biological sciences. With the cost of whole genome sequencing (WGS) approaching the much-anticipated $1000 level, it is now affordable to sequence the whole genome of hundreds to thousands of patients or healthy people. As a result, our knowledge of genome and its regulation in health and disease has increased tremendously: Since the completion of the Human Genome Project (HGP), millions of variants and mutations have been identified and thousands of them have been associated with both inherited and sporadic diseases. So far, an overwhelming majority of clinical genomics studies have focused on the “exome” – protein-coding parts of the genome, mainly due to its much lower cost compared to WGS. ENCODE (Encyclopedia of DNA Elements) Project and similar efforts have provided peek into the functional organization of the genome, however, our knowledge of how genomic information is utilized is far from complete and limited. A better understanding of such fundamental principles of genome regulation will undoubtedly help us explain the molecular basis of pathologic disease states. The overarching goal of our research efforts is to unravel these principles within the context of nervous system disorders.

Oktay Lab 1-2

RESEARCH INTERESTS

Our research has two main approaches:

1. Identification of disease causing variants/mutations: targeted sequencing of functional elements, RNA-seq, WES, as well as WGS will be utilized in the analysis of patient samples.

2. Functional studies on identified variants in cell culture and animal models: CRISPR-Cas9 based genome editing is planned to be used extensively to generate models.

Our efforts are focused on diseases of the nervous system:
1. Neurodevelopmental (autism spectrum disorders, epilepsy syndromes)
2. Neurooncological (gliomas)
3. Neurodegenerative (Inherited early-onset syndromes)

Autism Spectrum Disorders (ASDs) are among the most common neurodevelopmental disorders: 1 in 68 children in the USA are diagnosed with ASD. However, their clinical presentation is extremely heterogeneous, with deficits in social communication and interaction as the most prominent features. Recent genome-wide linkage and association studies have revealed that clinical heterogeneity is paralleled by genetic complexity. It has recently been shown that almost 70% of affected siblings carry different mutations, implicating that each child with ASD is “unique” and further studies are required to fully understand the molecular etiology of ASDs.

We are interested in identifying causal variants with the purpose of developing diagnostic and therapeutic tools.

Gliomas are the most common and deadliest type of primary brain tumors. Despite large-scale genomic efforts by consortiums such as The Cancer Genome Atlas (TCGA) have mapped the mutational landscape of gliomas, our knowledge on the processes of gliomagenesis is still scarce. On the other hand, Genome-Wide Association Studies (GWAS) have identified genomic loci/SNPs that are associated with increased glioma risk, however, the molecular basis of these associations are largely missing. Our studies aim to leverage information gained from these two different approaches to understanding the earliest steps of gliomagenesis.

Yavuz Oktay Şekil

 

RESEARCH HIGHLIGHTS

Our recent work on low-grade gliomas (LGGs) has focused on understanding the genetic basis of genetic predisposition to IDH-mutated gliomas, which comprise 70-80 % of LGGs. These studies were conducted by a multi-disciplinary approach that employed transcriptomic, proteomic, immunohistochemical, clinical and epidemiologic analyses of tumor and blood samples from LGG patients. A manuscript based on these studies is under review. Also, a TUBITAK 1001 grant has recently (2015) been awarded for 3 years to study the mechanistic basis of 8q24.21-associated genetic predisposition to glioma. Within this project, neural stem cell (NSC) lines are being edited by using the CRISPR-Cas9 system to obtain isogenic cell lines that differ at only the disease-associated variants/loci, in the absence and presence of IDH1-R132H mutation due to the strict association of these variants with IDH1/2 mutations. An integrated analysis of these cells will be carried out by 4C-seq, RNA-seq, enhancer assays, etc.

AWARDS AND RECOGNITION
• Young Scientist (BAGEP) Award 2013, by Science Academy (Turkey).
PUBLICATIONS
Full list and citations: Google Scholar: Yavuz Oktay

• Akyerli C., Yuksel S., Can O., Erson-Omay Z., Oktay Y., Cosgun E., Ulgen E., Erdemgil Y., San A., von Deimling A., Gunel M., Yakicier C., Pamir M.N., Ozduman K. Use of telomerase promoter mutations to mark specific molecular subsets with reciprocal clinical behavior in IDH mutant and IDH wild-type diffuse gliomas. Journal of Neurosurgery. 2017 Jun 16:1-13. doi: 10.3171/2016.11.JNS16973.
Oktay Y., Boylu C.A., Özduman K. Gliom Gelişiminde Genetik Yatkınlığın Rolü. Türk Nöroşirürji Dergisi. 2017 May 27(2):1-9.
• Pavlopoulou A., Oktay Y., Vougas K., Louka M., Vorgias C.E., Georgakilas A.G. Determinants of resistance to chemotherapy and ionizing radiation in breast cancer stem cells. Cancer Letters. 2016 Jul 19; 380(2):485-493. doi: 10.1016/j.canlet.2016.07.018. (IF: 5.99)
Oktay Y., Ülgen E., Can Ö., Akyerli C.B., Yüksel Ş., Erdemgil Y., Durası I.M., Henegariu O.I., Nanni E.P., Selevsek N., Grossmann J., Erson-Omay E.Z., Bai H., Gupta M., Lee W., Turcan Ş., Özpınar A., Huse J.T., Sav M.A., Flanagan A., Günel M., Sezerman O.U., Yakıcıer M.C., Pamir M.N. & Özduman K. IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation. Sci Rep. 2016 Jun 10; 6:27569. doi: 10.1038/srep27569.
• Zhang J, Khvorostov I, Hong J.S., Oktay Y., Vergnes L., Nuebel E., Wahjudi P.N., Setoguchi K., Wang G., Do A., Jung H.J., McCaffery J.M., Kurland I.J., Reue K., Lee W.N., Koehler C.M., Teitell M.A. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J. 2011;  30(24): 4860-4873.
• Wang G., Chen H.W., Oktay Y., Allen E.L., Smith G.M., Fan K.C., Hong J.S., French S.W., McCaffery J.M., Lightowlers R.M., Morse H.C., Koehler C.M., and Teitell M.A. PNPase regulates RNA import into mitochondria. Cell. 2010 Aug 6; 142(3):456-67.
• Claypool S.M., Oktay Y., Boontheung P., Loo J.A., Koehler C.M. Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane. J. Cell Biol. 2008 Sep 8; 182 (5): 937-50.
Oktay Y., Dioum E., Matsuzaki S., Ding K., Yan L.J., Haller R.G., Szweda L.I., and Garcia J.A. Hypoxia-inducible factor 2alpha regulates expression of the mitochondrial aconitase chaperone protein frataxin. J. Biol. Chem. 2007 Apr 20; 282: 11750-11756.
• Scortegagna M., Ding K., Zhang Q., Oktay Y., Bennett M.J., Bennett M., Shelton J.M., Richardson J.A., Moe O., and Garcia J.A. HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood. 2004; 105(8): 3133-40, Published: APR 15 2005.
• Scortegagna M., Ding K., Oktay Y., Gaur A., Thurmond F., Yan L.J. Marck B.T., Matsumoto A.M., Shelton J.M., Richardson J.A., Bennett M.J. Garcia J.A. Multiple organ pathology, metabolic ab-normalities and impaired homeostasis of reactive oxygen species in Epas1 -/- mice. Nature Genetics. 2003; 35(4): 331-40.
• Scortegagna M., Morris M.A., Oktay Y., Bennett M., Garcia J.A. The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice. Blood. 2003 Sep 1; 102(5): 1634-40.

BOOK CHAPTERS
Oktay Y. et al. Medical Genetics. In Current Applications of Biotechnology. Eds: Dundar M, Bruschi F, Deeni Y, Gahan P, Gartland KMA, Viola-Magni MP. Erciyes Üniversitesi, Kayseri, pp. 299-317. 2015. ISBN: 978-605-85573-0-1
Oktay Y., Boylu C.A., Özduman K., Sav M.A., Yakıcıer M.C. Gliomların Patolojisi ve Moleküler Biyolojik Özellikleri. Kanser Gündemi Dergisi, Beyin Tümörleri 1: Gliomlar. Eds: Pamir NM, Özduman K.Türkiye Kanserle Savaş Vakfı, İstanbul, Volume 2/3. pp. 17-22, 2014. ISSN: 0094-0143 (Turkish)
• Boylu C.A., Oktay Y., Can Ö., Özduman K., Yakıcıer M.C. Gliomların Moleküler Patogenezi. Kanser Gündemi Dergisi, Beyin Tümörleri 1: Gliomlar. Eds: Pamir NM, Özduman K. Türkiye Kanserle Savaş Vakfı, İstanbul, Volume 2/3 pp. 23-27, 2014. ISSN: 0094-0143 (Turkish)
• Yakıcıer MC, Ağırbaşlı D, Akyerli Boylu C, Oktay Y. Fonksiyonel Genomik. Moleküler Üroloji – Ürolojik Hastalıkların Moleküler Temeli Eds: Türkeri L, Özer A, Narter F. Üroonkoloji Derneği, İstanbul, pp. 191-203, 2012. ISBN: 978-975-01697-2-4 (Turkish)
Oktay Y., Rainey R.N., and Koehler C.M. The function of TIM22 in the insertion of inner membrane proteins in mitochondria. In The Enzymes (vol 25): Molecular Machines Involved in Protein Transport Across Membranes. Eds: Dalbey, R. E., Koehler, C. M., and Tamanoi, F. Academic Press, USA, 2007, pp. 367-386. ISBN: 978-0123739162.