Gelişmekte olan insan fetüslerinin ve yetişkinlerin derisinde EZH2 ekspresyonu: karşılaştırmalı bir çalışma

Year 2023, Volume: 48 Issue: 3, 1081 - 1089, 30.09.2023

Özge Zorlu , Sevil Karabağ , Kivilcim Erdogan , Evin Kuşsever , İlke Özer Aslan

https://doi.org/10.17826/cumj.1321745

Abstract

Amaç: Epigenetic düzenleyici olan Enhancer of zeste homolog 2 (EZH2), hayvanlarda deri ve eklerinin embriyonik gelişimi için gereklidir. Bu çalışmada, insan fetüslerinin deri örneklerinde EZH2 ekspresyon paternlerini, erişkinler ile karşılaştırmalı olarak araştırmayı amaçladık.
Gereç ve Yöntem: Altmış yedi fetüsün skalp bölgesinden ve 23 yetişkinin dudak wedge rezeksiyonunun en uzak cerrahi sınırından alınan, herhangi bir lezyon bulunmayan, deri örneklerinde EZH2 ile immünohistokimyasal boyama uygulandı. EZH2 skorları literatüre göre değerlendirildi.
Bulgular: Epidermal (r = - 0,528), dermal (rs = - 0,509) ve kıl folikülü (r = - 0,576) EZH2 skorları gebelik yaşı ile ters orantılıydı. Epidermal ve kıl folikülü EZH2 skorları erişkinlerde fetüslere göre anlamlı olarak daha yüksekti. Hem fetüs hem de erişkin dokularda epidermal, dermal ve kıl folikülü EZH2 skorları arasında anlamlı ve pozitif korelasyonlar saptandı.
Sonuç: Doğumdan önce nihai kutanöz farklılaşma ve olgunlaşma için daha düşük EZH2 seviyeleri gerekli olabilir. Bulgularımız, farklılaşma kusurları izlenen deri hastalıkları, kronik yaralar ve alopesiler üzerinde terapötik bir etkiye sahip olabilir.

Keywords

Fetüs, EZH2, deri, epidermis, dermis, kıl folikülü

Project Number

-

EZH2 expression in the skin of developing human fetuses and adults: a comparative study

Abstract

Purpose: In animals, the appropriate levels of Enhancer of zeste homolog 2 (EZH2), a well-established epigenetic regulator, are essential for the embryonic development of skin and appendages. We aimed to explore the EZH2 expression patterns in the skin of human fetuses and compare them with adults.
Materials and Methods: We performed EZH2 immunohistochemical staining in skin samples from the scalp region of 67 fetuses and from the farthest surgical margin of the lip wedge resection, where no lesions were found, of 23 adults. EZH2 scores were evaluated according to the literature.
Results: Epidermal (r = − 0.528), dermal (rs = − 0.509), and hair follicle (r = − 0.576) EZH2 scores were inversely correlated with gestational age. Epidermal and hair follicle EZH2 scores were significantly higher in adults compared to fetuses. There were significant and positive correlations between epidermal, dermal, and hair follicle EZH2 scores among fetuses and adults.
Conclusion: Lower levels of EZH2 may be necessary for final cutaneous differentiation and maturation before birth. Our findings may have a therapeutic impact on cutaneous disorders with differentiation defects, chronic wounds, and alopecias.

Keywords

Fetus, EZH2, skin, epidermis, dermis, hair follicle

Supporting Institution

N/A

Project Number

-

Thanks

-

References

• Zhao X, Wu X. Polycomb-group proteins in the initiation and progression of cancer. J Genet Genomics. 2021;48:433-43.
• Thulabandu V, Nehila T, Ferguson JW, Atit RP. Dermal EZH2 orchestrates dermal differentiation and epidermal proliferation during murine skin development. Dev Biol. 2021;478:25-40.
• Tan B, Hong L, Qiao J, Zhou J, Xing P, Yan G et al. Identification and expression pattern of EZH2 in pig developing fetuses. Biomed Res Int. 2020;2020:5315930.
• Loh JT, Lim T, Ikumi K, Matoba T, Janela B, Gunawan M et al. Ezh2 controls skin tolerance through distinct mechanisms in different subsets of skin dendritic cells. iScience. 2018;10:23-39.
• Ezhkova E, Pasolli HA, Parker JS, Stokes N, Su I, Hannon G et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009;136:1122-35.
• Chen D, Jarrell A, Guo C, Lang R, Atit R. Dermal β-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation. Development. 2012;139:1522-33.
• Fu J, Hsu W. Epidermal Wnt controls hair follicle induction by orchestrating dynamic signaling crosstalk between the epidermis and dermis. J Invest Dermatol. 2013;133:890-8.
• Werner S, Krieg T, Smola H. Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol. 2007;127:998-1008.
• Wurm S, Zhang J, Guinea-Viniegra J, Garcia F, Munoz J, Bakiri L et al. Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2. Genes Dev. 2015;29:144-56.
• Sen GL, Webster DE, Barragan DI, Chang HY, Khavari PA. Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev. 2008;22:1865-70.
• Ezhkova E, Lien WH, Stokes N, Pasolli HA, Silva JM, Fuchs E. EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev. 2011;25:485-98.
• Shaw T, Martin P. Epigenetic reprogramming during wound healing: loss of polycomb-mediated silencing may enable upregulation of repair genes. EMBO Rep. 2009;10:881-6.
• Plikus MV, Guerrero-Juarez CF, Treffeisen E, Gay DL. Epigenetic control of skin and hair regeneration after wounding. Exp Dermatol. 2015;24:167-70.
• Qu S, Liu Z, Wang B. EZH2 is involved in psoriasis progression by impairing miR-125a-5p inhibition of SFMBT1 and leading to inhibition of the TGFβ/SMAD pathway. Ther Adv Chronic Dis. 2021;12:2040622320987348.
• Zhang T, Yang L, Ke Y, Lei J, Shen S, Shao S et al. EZH2-dependent epigenetic modulation of histone H3 lysine-27 contributes to psoriasis by promoting keratinocyte proliferation. Cell Death Dis. 2020;11:826.
• Yu J, Tang R, Ding K. Epigenetic modifications in the pathogenesis of systemic sclerosis. Int J Gen Med. 2022;15:3155-66.
• Tsou PS, Campbell P, Amin MA, Coit P, Miller S, Fox DA et al. Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in scleroderma. Proc Natl Acad Sci U S A. 2019;116:3695-702.
• Krämer M, Dees C, Huang J, Schlottmann I, Palumbo-Zerr K, Zerr P et al. Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann Rheum Dis. 2013;72:614-20.
• Wasson CW, Abignano G, Hermes H, Malaab M, Ross RL, Jimenez SA et al. Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Ann Rheum Dis. 2020;79:507-17.
• Yang Y, Liu K, Liu M, Zhang H, Guo M. EZH2: Its regulation and roles in immune disturbance of SLE. Front Pharmacol. 2022;13:1002741.
• Eich ML, Athar M, Ferguson JE, Varambally S. EZH2-targeted therapies in cancer: hype or a reality. Cancer Res. 2020;80:5449-58.
• Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol. 2020;13:104.
• Uebel A, Kewitz-Hempel S, Willscher E, Gebhardt K, Sunderkötter C, Gerloff D. Resistance to BRAF inhibitors: EZH2 and its downstream targets as potential therapeutic options in melanoma. Int J Mol Sci. 2023;24:1963.
• Veija T, Kero M, Keljonen V, Böhling T. ALK and EGFR expression by immunohistochemistry are associated with merkel cell polyomavirus status in merkel cell carcinoma. Histopathology. 2019;74:829-35.
• Liu H, Lin W, Liu Z, Song Y, Cheng H, An H et al. E3 ubiquitin ligase NEDD4L negatively regulates keratinocyte hyperplasia by promoting GP130 degradation. EMBO Rep. 2021;22:e52063.
• Müller A, Dickmanns A, Resch C, Schäkel K, Hailfinger S, Dobbelstein M et al. The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis. J Clin Invest. 2020;130:5765-81.
• Kang S, Chovatiya G, Tumbar T. Epigenetic control in skin development, homeostasis and injury repair. Exp Dermatol. 2019;28:453-63.
• Koyanagi M, Baguet A, Martens J, Margueron R, Jenuwein T, Bix M. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J Biol Chem. 2005;280:31470-7.
• Gunawan M, Venkatesan N, Loh JT, Wong JF, Berger H, Neo WH et al. The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat Immunol. 2015;16:505-16.
• Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol. 2002;118:216-25.
• Kobielak K, Kandyba E, Leung Y. Skin and skin appendage regeneration. In Translational Regenerative Medicine, (Eds Atala A, Allickson JG): 269-92. Boston, Academic Press, 2015.
• Silva LMA, Hsieh R, Lourenço SV, Rocha BO, Romiti R, Valente NYS et al. Revisiting hair follicle embryology, anatomy and the follicular cycle. J Cosmo Trichol. 2019;5:141.
• Yeliur I, Tirumalae R. Histopathologic approach to alopecia. Indian J Dermatopathol Diagn Dermatol. 2018;5:79-88.