Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - WoS: 6Citation - Scopus: 5Epitranscriptomics M6a Analyses Reveal Distinct M6a Marks Under Tumor Necrosis Factor Α (tnf-Α) Apoptotic Conditions in Hela Cells(Wiley, 2024) Akçaöz Alasar, Azime; Tuncel, Özge; Sağlam, Buket; Gazaloğlu, Yasemin; Atbinek, Melis; Çağıral, Umut; İşcan, Evin; Özhan, Güneş; Akgül, BünyaminTumor necrosis factor-alpha (TNF-alpha) is a ligand that induces both intrinsic and extrinsic apoptotic pathways in HeLa cells by modulating complex gene regulatory mechanisms. However, the full spectrum of TNF-alpha-modulated epitranscriptomic m(6)A marks is unknown. We employed a genomewide approach to examine the extent of m(6)A RNA modifications under TNF-alpha-modulated apoptotic conditions in HeLa cells. miCLIP-seq analyses revealed a plethora of m(6)A marks on 632 target mRNAs with an enrichment on 99 mRNAs associated with apoptosis. Interestingly, the m(6)A RNA modification patterns were quite different under cisplatin- and TNF-alpha-mediated apoptotic conditions. We then examined the abundance and translational efficiencies of several mRNAs under METTL3 knockdown and/or TNF-alpha treatment conditions. Our analyses showed changes in the translational efficiency of TP53INP1 mRNA based on the polysome profile analyses. Additionally, TP53INP1 protein amount was modulated by METTL3 knockdown upon TNF-alpha treatment but not CP treatment, suggesting the existence of a pathway-specific METTL3-TP53INP1 axis. Congruently, METLL3 knockdown sensitized HeLa cells to TNF-alpha-mediated apoptosis, which was also validated in a zebrafish larval xenograft model. These results suggest that apoptotic pathway-specific m(6)A methylation marks exist in cells and TNF-alpha-METTL3-TP53INP1 axis modulates TNF-alpha-mediated apoptosis in HeLa cells.Article Citation - WoS: 8Citation - Scopus: 8Canonical Wnt and Tgf-β/Bmp Signaling Enhance Melanocyte Regeneration but Suppress Invasiveness, Migration, and Proliferation of Melanoma Cells(Frontiers Media S.A., 2023) Katkat, Esra; Demirci, Yeliz; Heger, Guillaume; Karagülle, Doğa; Papatheodorou, Irene; Brazma, Alvis; Özhan, GüneşMelanoma is the deadliest form of skin cancer and develops from the melanocytes that are responsible for the pigmentation of the skin. The skin is also a highly regenerative organ, harboring a pool of undifferentiated melanocyte stem cells that proliferate and differentiate into mature melanocytes during regenerative processes in the adult. Melanoma and melanocyte regeneration share remarkable cellular features, including activation of cell proliferation and migration. Yet, melanoma considerably differs from the regenerating melanocytes with respect to abnormal proliferation, invasive growth, and metastasis. Thus, it is likely that at the cellular level, melanoma resembles early stages of melanocyte regeneration with increased proliferation but separates from the later melanocyte regeneration stages due to reduced proliferation and enhanced differentiation. Here, by exploiting the zebrafish melanocytes that can efficiently regenerate and be induced to undergo malignant melanoma, we unravel the transcriptome profiles of the regenerating melanocytes during early and late regeneration and the melanocytic nevi and malignant melanoma. Our global comparison of the gene expression profiles of melanocyte regeneration and nevi/melanoma uncovers the opposite regulation of a substantial number of genes related to Wnt signaling and transforming growth factor beta (TGF-beta)/(bone morphogenetic protein) BMP signaling pathways between regeneration and cancer. Functional activation of canonical Wnt or TGF-beta/BMP pathways during melanocyte regeneration promoted melanocyte regeneration but potently suppressed the invasiveness, migration, and proliferation of human melanoma cells in vitro and in vivo. Therefore, the opposite regulation of signaling mechanisms between melanocyte regeneration and melanoma can be exploited to stop tumor growth and develop new anti-cancer therapies.Article Citation - WoS: 7Citation - Scopus: 6Addition of Exogenous Diacylglycerol Enhances Wnt/Β-catenin Signaling Through Stimulation of Macropinocytosis(Elsevier, 2023) Azbazdar, Yağmur; Tejeda-Munoz, Nydia; Monka, Julia C.; Dayrit, Alex; Binder, Grace; De Robertis, Edward M.; Özhan, GüneşActivation of Wnt signaling triggers macropinocytosis and drives many tumors. We now report that the exogenous addition of the second messenger lipid sn-1,2 DAG to the culture medium rapidly induces macropinocytosis. This is accompanied by potentiation of the effects of added Wnt3a recombinant protein or the glycogen synthase kinase 3 (GSK3) inhibitor lithium chloride (LiCl, which mimics Wnt signaling) in luciferase transcriptional reporter assays. In a colorectal carcinoma cell line in which mutation of adenomatous polyposis coli (APC) causes constitutive Wnt signaling, DAG addition increased levels of nuclear β-catenin, and this increase was partially inhibited by an inhibitor of macropinocytosis. DAG also expanded multivesicular bodies marked by the tetraspan protein CD63. In an in vivo situation, microinjection of DAG induced Wnt-like twinned body axes when co-injected with small amounts of LiCl into Xenopus embryos. These results suggest that the DAG second messenger plays a role in Wnt-driven cancer progression. © 2023 The Author(s)Article Citation - WoS: 7Citation - Scopus: 8High-Fat Diet Feeding Triggers a Regenerative Response in the Adult Zebrafish Brain(Springer, 2023) Azbazdar, Yağmur; Poyraz, Yusuf Kaan; Özalp, Özgün; Nazlı, Dilek; İpekgil, Doğaç; Cucun, GÖkhan; Özhan, GüneşNon-alcoholic fatty liver disease (NAFLD) includes a range of liver conditions ranging from excess fat accumulation to liver failure. NAFLD is strongly associated with high-fat diet (HFD) consumption that constitutes a metabolic risk factor. While HFD has been elucidated concerning its several systemic effects, there is little information about its influence on the brain at the molecular level. Here, by using a high-fat diet (HFD)-feeding of adult zebrafish, we first reveal that excess fat uptake results in weight gain and fatty liver. Prolonged exposure to HFD induces a significant increase in the expression of pro-inflammation, apoptosis, and proliferation markers in the liver and brain tissues. Immunofluorescence analyses of the brain tissues disclose stimulation of apoptosis and widespread activation of glial cell response. Moreover, glial activation is accompanied by an initial decrease in the number of neurons and their subsequent replacement in the olfactory bulb and the telencephalon. Long-term consumption of HFD causes activation of Wnt/β-catenin signaling in the brain tissues. Finally, fish fed an HFD induces anxiety, and aggressiveness and increases locomotor activity. Thus, HFD feeding leads to a non-traumatic brain injury and stimulates a regenerative response. The activation mechanisms of a regeneration response in the brain can be exploited to fight obesity and recover from non-traumatic injuries.