1. Home
  2. Research
  3. BASIC AND TRANSLATIONAL RESEARCH PROGRAM
  4. Alotaibi Lab. on Transcriptional Regulation


BASIC AND TRANSLATIONAL RESEARCH PROGRAM
Alotaibi Lab. Angelov Lab. Atabey Lab. Gene Targeting and Transgenic Models Platform Genc Lab. Kale Lab. Karaca Lab. Oktay Lab. Ozhan Lab. Pavlopoulou Lab. Sag Lab. Senturk Lab. Wingender Lab. MG Lab. THORLAB Erkek Lab. BG Lab. Özbek Lab.

Alotaibi Lab. on Transcriptional Regulation

OVERVIEW

The epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET) are crucial for proper embryonic development but are also exploited by tumor cells. Tumor cells of epithelial origin can benefit from an EMT event and lose their epithelial and polarized morphology and gain mesenchymal unpolarized cell morphology. These cells can now cross the blood barrier, relocate and colonize sites in distant organs. Eventually, they will initiate MET to become epithelial-like and successfully form secondary tumors. Induction of EMT is integrated by many different signals but shares the activation of intracellular EMT-inducers like Snail, Slug, Zeb1 and others, which are transcription factors acting as repressors of the Ca2+-dependent adhesion molecule (E-cadherin), which is at the center of EMT-MET, its expression must be successfully downregulated for EMT to proceed, and must be rapidly restored for proper MET.

To date, MET is considered as a reverse process of EMT. However, MET is not simply the reverse process of EMT. It is a complicated and dynamic process. There must be a more complex regulatory mechanisms ensuring the establishment of an epithelial phenotype. This dynamic MET process can only in part be explained by the upregulation and downregulation of EMT inducers. It suggests the presence of other transcriptional activators for E-cadherin, which could also be regulators of MET.

RESEARCH INTERESTS

We are interested in understanding the genetic and molecular mechanisms of tumorigenesis, with a focus on dissecting the transcriptional networks controlling the mesenchymal to epithelial transition.

Transcriptional networks have been described before; examples include, but are not limited to, the transcriptional network of EMT, the core pluripotency network of embryonic stem cells, and the transcriptional network of blood stem cells. There are different kinds (or motifs) of transcriptional regulatory networks. These are sets of transcription factors that control the initiation and maintenance of certain transcriptional loops or chains to augment or stabilize gene expression. Examples of the network motifs include for example autoregulatory loops, where a transcription factor would be regulating its own expression, such as the Nanog loop in the core pluripotency network. In feed forward loops, transcription factor X will regulate both Gene Y and Gene Z, where Gene Y encodes a transcription factor that also regulates Gene-Z, an example of such regulatory loop comes from our recent study describing the initiation of MET, in which Grhl3 regulates the expression of both Cdh1 and Hnf4a, Hnf4a is then recruited to the Cdh1 chromatin to boost up the Grhl3-dependent regulation. In a multi-component loop, transcription factors regulate the expression of their regulators in a positive feedback loop; a very well-known example is the closed circuit of Oct4/Sox2 in embryonic stem cells regulatory network. In a regulatory chain, three or more transcription factors are ordered in a series, the chain ends when the transcription factor has no target (i.e. no transcription factor target) or is autoregulatory, an example of such regulatory chains comes from the hematopoietic stem cells, where b-catenin regulates HoxB4, which in turn activates the expression of c-myc. Common to most transcriptional network studies is the methodology used; most share similar sets of experimental and knowledge-based approaches, combining data mining, gene expression profiling and gene silencing, all integrated into a powerful computational analysis to correctly decipher transcriptional nodes and network motifs.

In order to validate the existence of an MET network, we will investigate in detail the expression profiles of several EMT-MET cellular models; including NMuMG cells as well as human cancer cell line models that are known to undergo mesenchymal to epithelial transition. We will use an integrated approach, including data mining, high throughput expression profiling, gene silencing, and validation by protein-protein and protein-DNA interaction techniques. As a result, we anticipate defining an epithelial state specific transcription factor gene set. Using this gene set we will continue to define the relationships between the members and their function within a network. Our preliminary data suggest the existence of several overlapping transcriptional nodes having Grhl3 in the center of a larger network and E-cadherin as the major outcome. Our main goal is to confirm the transcriptional relationships between the identified transcription factors and to draw a more comprehensive picture of the MET network. As a result, we aim to identify a core MET network, which, in the long run, may lead to the identification of therapeutic targets for the control of MET during metastasis. MET is also a critical step during the reprogramming of iPSCs, thus identifying a core MET network could be utilized to improve the efficiency and quality of the reprogramming process.

RESEARCH HIGHLIGHTS

To date, there is a substantial amount of data in the literature analyzing the EMT program both during embryonic development and also during tumorigenesis, but a similar understanding of the MET program is still lagging. Recently we have identified a feed forward loop, which is composed of the transcription factors Grhl3 and Hnf4a that is essential for the progression of MET. In fact, Grhl3 emerged as an absolute requirement for the initiation of MET. Cells lacking Grhl3 as a result of RNAi-mediated knockdown failed to initiate the MET program. This is in part due to their inability to upregulate E-cad expression. Furthermore, we found that Grhl3 contributes to the regulation of Hnf4α by binding to a well-conserved motif present within the Hnf4α promoter P2. We believe that there is a need to gather more credible scientific evidence that answers key questions regarding how the process of MET is regulated, how it is initiated and the transcription factors involved in this regulation.

Group Members

Alotaibi Lab. on Transcriptional Regulation

Research Group Leader

Hani ALOTAİBİ
hani.alotaibi@ibg.edu.tr
+90 232 299 41 00 (5071)
 +9 0 232 299 41 57

  1. Alotaibi Lab. on Transcriptional Regulation

Canan Büşra ERSAYAR Research Technician  canan.ersayar@ibg.edu.tr


İNCİ YAPRAK MSc Student  inci.yaprak@ibg.edu.tr


Gkamze IMPRAIMOGLOU KAFAZ MSc Student  gkamze.impraimoglou@ibg.edu.tr


Şehriban BÜYÜKKILIÇ PhD Student  sehriban.buyukkilic@ibg.edu.tr


Zehra Yağmur ALAGÖZ Undergraduate Student  zehra.alagoz@ibg.edu.tr


Esin ŞEKEROĞLU PhD Student  esin.ozkuru@ibg.edu.tr


Seray YETKİN PhD Student  seray.yetkin@ibg.edu.tr


Cemre Su YENİCELİ Undergraduate Student  cemresu.yeniceli@ibg.edu.tr


ŞEYMA NUR YILDIZ PhD Student  seyma.yildiz@ibg.edu.tr


Zeynep KARAGÖZ MSc Student  zeynep.karagoz@ibg.edu.tr


Hilal ÇAĞLAYAN PhD Student  hilal.caglayan@std.ibg.edu.tr


Helin SAĞIR PhD Student  helin.sagir@ibg.edu.tr


Elif Bilge KİRİŞ Undergraduate Student  elif.kiris@std.ibg.edu.tr


İNCİ YAPRAK PhD Student  inci.yaprak@ibg.edu.tr


İNCİ YAPRAK PhD Student  inci.yaprak@ibg.edu.tr


İNCİ YAPRAK PhD Student  inci.yaprak@ibg.edu.tr


Esra DİNCASLAN MSc Student  esra.dincaslan@std.ibg.edu.tr


Former Members

Burcu ŞENGEZ Research Assistant  burcu.sengez@ibg.edu.tr


Nazlıhan ASTOPAL Visiting Researcher 


Hadi ROUHRAZİ Post-Doc Researcher  hadi.rouhrazi@ibg.edu.tr


Tuğşen AYDEMİR Post-Doc Researcher  tugsen.aydemir@msfr.ibg.edu.tr


Naz ŞERİFOĞLU MSc Student  naz.serifoglu@msfr.ibg.edu.tr


Çağrı BULDU MSc Student  cagri.buldu@msfr.ibg.edu.tr


Diana ZEID MSc Student  diana.zeid@msfr.ibg.edu.tr


Caner YARIMÇAM PhD Student  caner.yarimcam@msfr.ibg.edu.tr


Gürkan AKYILDIZ Post-Doc Researcher  gurkan.akyildiz@msfr.ibg.edu.tr


Hazal AYTEKİN PhD Student  hazal.aytekin@msfr.ibg.edu.tr


İrem KÜLLÜ Undergraduate Student  irem.kullu@msfr.ibg.edu.tr


Tuğçe YAPAR PhD Student  tugce.yapar@ibg.edu.tr


Ayça ÖZKAN MSc Student  ayca.ozkan@ibg.edu.tr

0 (232) 299 _ _

Şimal KAYIKÇI Undergraduate Student  simal.kayikci@ibg.edu.tr


Helin SAĞIR PhD Student  helin.sagir@ibg.edu.tr


Seray YETKİN MSc Student  seray.yetkin@ibg.edu.tr


Sevgi ERDEM Visiting Researcher  sevgi.erdem@ibg.edu.tr


İLAYDA KAYA Undergraduate Student  ilayda.kaya@msfr.ibg.edu.tr


Filiz ŞAHİN MSc Student  filiz.sahin@ibg.edu.tr


Doğa ESKİER PhD Student  doga.eskier@ibg.edu.tr


Nilüfer DÜZ PhD Student  nilufer.duz@ibg.edu.tr


Selected Publications

Doğa Eskier, Seray Yetkin, Nazmiye Arslan, Gökhan Karakülah, Hani Alotaibi. Exploring Regulatory Roles of Transposable Elements in EMT and MET through Data-Driven Analysis: Insights from regulaTER. Journal of Molecular Biology. 2025 January ; 437 (2) : 168887. doi:10.1016/j.jmb.2024.168887. Download

Abu Alhaija AA, Lone IN, Ozkuru Sekeroglu E, Batur T, Angelov D, Dimitrov S, Hamiche A, Firat Karalar EN, Ercan ME, Yagci T, Alotaibi H, Diril MK. Development of a mouse embryonic stem cell model for investigating the functions of the linker histone H1-4.. FEBS open bio. 2024 February . doi:10.1002/2211-5463.13750. Download

Alotaibi H, Meuwissen R, Sayan AE. Editorial: Understanding the mesenchymal to epithelial transition: a much needed angle for epithelial mesenchymal plasticity.. Frontiers in cell and developmental biology. 2024 October ; 12 : 1497515. doi:10.3389/fcell.2024.1497515. Download

Alotaibi H. The transcription factor ELF5 is essential for early preimplantation development.. Molecular biology reports. 2023 March ; 50 : 2119-2125. doi:10.1007/s11033-022-08217-z. Download

Yetkin S, Alotaibi H. Selection and validation of novel stable reference genes for qPCR analysis in EMT and MET.. Experimental cell research. 2023 July ; 428 (1) : 113619. doi:10.1016/j.yexcr.2023.113619. Download

Demir AB, Baris E, Kaner UB, Alotaibi H, Atabey N, Koc A. Toll-interacting protein may affect doxorubicin resistance in hepatocellular carcinoma cell lines.. Molecular biology reports. 2023 August . doi:10.1007/s11033-023-08737-2. Download

Sengez B, Carr BI, Alotaibi H. EMT and Inflammation: Crossroads in HCC.. Journal of gastrointestinal cancer. 2022 January . doi:10.1007/s12029-021-00801-z. Download

Toyran N. Alotaibi H.. Evaluating The Transcriptional Regulation of Cdh1 by Grhl3 in Different Cellular Models. Journal of The Institute of Science and Technology. 2022 March ; 12 (1) : 446-454. doi:10.21597/jist.963916. Download

Hani Alotaibi. Crif1 is Required for Proper Mesenchymal to Epithelial Transition. Cumhuriyet Science Journal. 2022 January ; 43 (2) : 165. doi:10.17776/csj.1062126. Download

Evin Iscan, Umut Ekin, Gokhan Yildiz, Ozden Oz, Umur Keles, Aslı Suner, Gulcin Cakan-Akdogan, Gunes Ozhan, Marta Nekulova, Borivoj Vojtesek, Hamdiye Uzuner, Gökhan Karakülah, Hani Alotaibi and Mehmet Ozturk. TAp73β Can Promote Hepatocellular Carcinoma Dedifferentiation. Cancers. 2021 February ; 13 (4) : 783. doi:10.3390/cancers13040783. Download

Toy HI, Karakülah G, Kontou PI, Alotaibi H, Georgakilas AG, Pavlopoulou A. Investigating Molecular Determinants of Cancer Cell Resistance to Ionizing Radiation Through an Integrative Bioinformatics Approach.. Frontiers in cell and developmental biology. 2021 April ; 9 : 770. doi:10.3389/fcell.2021.620248. Download

Tugce Batur, Ayse Argundogan, Umur Keles, Zeynep Mutlu, Hani Alotaibi, Serif Senturk, Mehmet Ozturk. AXL knock-out in SNU475 hepatocellular carcinoma cells provides evidence for lethal effect associated with G2 arrest and polyploidization. International Journal of Molecular Sciences. 2021 December ; 22 (24) : 13247. doi:10.3390/ijms222413247. Download

Hani Alotaibi. Transcriptional impact of E-cadherin loss on embryonic stem cells. Jordan Journal of Biological Sciences. 2021 December ; 14 (5) . doi:10.54319/jjbs/140524. Download

Ekin U, Yuzugullu H, Ozen C, Korhan P, Bagirsakci E, Yilmaz F, Yuzugullu OG, Uzuner H, Alotaibi H, Kirmizibayrak PB, Atabey N, Karakülah G, Ozturk M. Evaluation of ATAD2 as a Potential Target in Hepatocellular Carcinoma.. Journal of gastrointestinal cancer. 2021 November . doi:10.1007/s12029-021-00732-9. Download

Lone IN, Sengez B, Hamiche A, Dimitrov S, Alotaibi H. The Role of Histone Variants in the Epithelial-To-Mesenchymal Transition.. Cells. 2020 November ; 9 (11) . doi:10.3390/cells9112499. Download

Sengez B, Aygün I, Shehwana H, Toyran N, Tercan Avci S, Konu O, Stemmler MP, Alotaibi H. The Transcription Factor Elf3 Is Essential for a Successful Mesenchymal to Epithelial Transition.. Cells. 2019 August ; 8 (8) . doi:10.3390/cells8080858. Download

Alotaibi H, Tuzlakoğlu-Öztürk M, Tazebay UH. The Thyroid Na+/I- Symporter: Molecular Characterization and Genomic Regulation. MOLECULAR IMAGING AND RADIONUCLIDE THERAPY. 2017 February ; 26 (1) : 92-101. doi:10.4274/2017.26.suppl.11. Download

İmge KUNTER, Emine KANDEMİŞ, Hani ALOTAİBİ, Tülay CANDA, Esra ERDAL BAĞRIYANIK. Alteration in the subcellular location of the inhibitor of growth protein p33(ING1b) in estrogen receptor alpha positive breast carcinoma cells. Turkish Journal of Biology. 2017 ; 41 (1) : 105-112. doi:10.3906/biy-1602-95 . Download

Alotaibi H, Basilicata MF, Shehwana H, Kosowan T, Schreck I, Braeutigam C, Konu O, Brabletz T, Stemmler MP. Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition. Biochimica et biophysica acta. 2015 June ; 1849 (6) : 731-42. doi:10.1016/j.bbagrm.2015.01.005. Download

Bedzhov I, Alotaibi H, Basilicata MF, Ahlborn K, Liszewska E, Brabletz T, Stemmler MP. Adhesion, but not a specific cadherin code, is indispensable for ES cell and induced pluripotency.. Stem cell research. 2013 November ; 11 (3) : 1250-63. doi:10.1016/j.scr.2013.08.009. Download

Telkoparan P, Erkek S, Yaman E, Alotaibi H, Bayık D, Tazebay UH. Coiled-coil domain containing protein 124 is a novel centrosome and midbody protein that interacts with the Ras-guanine nucleotide exchange factor 1B and is involved in cytokinesis.. PloS one. 2013 July ; 8 (7) : e69289. doi:10.1371/journal.pone.0069289. Download

Mumcuoglu M, Bagislar S, Yuzugullu H, Alotaibi H, Senturk S, Telkoparan P, Gur-Dedeoglu B, Cingoz B, Bozkurt B, Tazebay UH, Yulug IG, Akcali KC, Ozturk M. The ability to generate senescent progeny as a mechanism underlying breast cancer cell heterogeneity.. PloS one. 2010 June ; 5 (6) : e11288. doi:10.1371/journal.pone.0011288. Download

Alotaibi H, Yaman E, Salvatore D, Di Dato V, Telkoparan P, Di Lauro R, Tazebay UH. Intronic elements in the Na+/I- symporter gene (NIS) interact with retinoic acid receptors and mediate initiation of transcription.. Nucleic acids research. 2010 June ; 38 (10) : 3172-85. doi:10.1093/nar/gkq023. Download

Alotaibi H, Ricciardone MD, Ozturk M. Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia.. Mutation research. 2008 January ; 637 (1-2) : 209-14. doi:10.1016/j.mrfmmm.2007.08.003. Download

Alotaibi H, Yaman EC, Demirpençe E, Tazebay UH. Unliganded estrogen receptor-alpha activates transcription of the mammary gland Na+/I- symporter gene.. Biochemical and biophysical research communications. 2006 July ; 345 (4) : 1487-96. doi:10.1016/j.bbrc.2006.05.049. Download

Total : 25

Selected Book Chapters

TRANSCRIPTIONAL REGULATION OF EPITHELIAL-TO-MESENCHYMAL TRANSITION BY TGFb ISOFORMS (2021). RESEARCH & REVIEWS IN HEALTH SCIENCES. Gece Kitaplığı.

Kodom Optimizasyonu Ve Rekombinant Protein Üretimindeki Yeri (2021). PROTEİN: YAPISI, MÜHENDİSLİĞİ, ETKİLEŞİMLERİ, DİNAMİĞİ VE İLAÇ TASARIMINDAKİ YERİ. Ankara Nobel Tıp Yayınevi.

Molecular Mechanisms of Hepatocellular Carcinoma (2016). Hepatocellular Carcinoma: Diagnosis and Treatment, 3rd Edition. Springer.

Total : 3

Projects

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Kanser ve Osteoporoz Tedavisi İçin Monoklonal Antikor Etkin Maddeli Biyobenzer İlaç Geliştirilmesi ve Üretilmesi, Ongoing

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Mezenkimal-Epitelyal Dönüşümünü (Met) Kontrol Eden Transkripsiyonel Ağların Belirlenmesi, Finished

DEÜ BAP - Dokuz Eylul University Scientific Research Projects Coordination Unit - RD : Mezenkimal-Epiteliyal Sürecinde ELF3'ün GRHL3 Ekspresyonuna Olan Etkisinin Belirlenmesi, Finished

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Identification of Transcription Factors Influencing the Epigenetic Reprogramming During the Mesenchymal to Epithelial Transition (MET), Finished

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Epigenetics of Epithelial-to-Mesenchymal and Mesenchymal-to-Epithelial Transitions : Role of Histone Variants and Pioneer Transcription Factors, Ongoing

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Functional Analysis of Long Non-coding RNAs Critical for the Mesenchymal to Epithelial Transition, Ongoing

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : HepatoselülerKarsinoma Hücre Hatlarının Doksorubisin Hassasiyetini Arttırmaya Yönelik TOLLIP Geninin Doksorubisin Dirençliliğindeki Rolünün Belirlenmesi, Ongoing

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Epigenetics of the Mesenchymal to Epithelial Transition, Ongoing

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Development of a Computational Tool to Predict Transposable Elements With Gene Regulatory Roles and Identification of Transposable Elements That Are Involved in to Mesenchymal – Epithelial Transition, Ongoing

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Mezenkimal Epitelyal Dönüşüm Sürecinde Rol Alan mikroRNA'ların Tanımlanması ve Fonksiyonel Analizleri, Ongoing

The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Sağlıkta ve Rahman Sendromunda Bağlayıcı Histon H1E, Ongoing

DEÜ BAP - Dokuz Eylul University Scientific Research Projects Coordination Unit - RD : Kanser ve metastaz oluşumunda Elf5 genin rolünün, E-cadherin üzerindeki regülasyonu ve EMT/MET kontrol mekanizmasının araştırılması., Ongoing

Awards

  • Project Performance Award by TUBITAK, 2021
  • Short Term Fellowship by EMBO, 2005

Academic Memberships

  • Biochemical Society, 2000

Contact

Alotaibi Lab. on Transcriptional Regulation

Research Group Leader

Hani ALOTAİBİ
hani.alotaibi@ibg.edu.tr
+90 232 299 41 00 (5071)
 +9 0 232 299 41 57