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A ZFP42/MARK2 regulatory network reduces the damage of retinal ganglion cells in glaucoma: a study based on GEO dataset and in vitro experiments

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Abstract

Glaucoma is a common disorder in which the death of retinal ganglion cells (RGCs) results in a progressive loss of sight, even blindness. This study was performed to reveal the key molecular mechanism of RGC damage in glaucoma based on the Gene Expression Omnibus database. Glaucoma-related microarray datasets were identified, followed by collection of differentially expressed genes (DEGs) with the key genes discovered by weighted gene co-expression network analysis. Through LASSO regression analysis, candidate genes involved in the pathogenesis of glaucoma were identified with their accuracy evaluated by receiver operating characteristic curve analysis. The glaucoma-specific transcriptional regulatory network was constructed to determine the key transcription factor regulatory axis. Then, in vitro cell models were established using H2O2 for further verifying the regulatory role of identified ZFP42/MARK2 axis in RGC damage in glaucoma. Differential analysis of GSE27276, GSE45570, and GSE101727 microarray datasets yielded 165 DEGs, and 22 key genes were identified following. Then, 9 candidate genes involved in the pathogenesis of glaucoma was collected and the key ZFP42/MARK2 regulatory axis was found. In vitro cell experiments further confirmed that ZFP42 and MARK2 were down-regulated in RGCs treated with H2O2. In addition, overexpression of ZFP42 increased the expression of MARK2 to increase RGC cell viability, and reduce cell apoptosis and ROS levels, while silencing MARK2 could reverse the protective effect of ZFP42. We confirmed that ZFP42 reduced the damage of RGCs in glaucoma by up-regulating the expression of MARK2.

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The data and materials of the study can be obtained from the corresponding author upon request.

References

  1. Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, PandaJonas S (2017) Glaucoma. Lancet 390:2183–2193. https://doi.org/10.1016/S0140-6736(17)31469-1

    Article  PubMed  Google Scholar 

  2. Kang JM, Tanna AP (2021) Glaucoma. Med Clin N Am 105:493–510. https://doi.org/10.1016/j.mcna.2021.01.004

    Article  PubMed  Google Scholar 

  3. Weinreb RN, Aung T, Medeiros FA (2014) The pathophysiology and treatment of glaucoma: a review. JAMA 311:1901–1911. https://doi.org/10.1001/jama.2014.3192

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. McMonnies CW (2017) Glaucoma history and risk factors. J Optom 10:71–78. https://doi.org/10.1016/j.optom.2016.02.003

    Article  PubMed  Google Scholar 

  5. Conlon R, Saheb H, Ahmed II (2017) Glaucoma treatment trends: a review. Can J ophthalmol J Can d’ophtalmol 52:114–124. https://doi.org/10.1016/j.jcjo.2016.07.013

    Article  Google Scholar 

  6. He S, Stankowska DL, Ellis DZ, Krishnamoorthy RR, Yorio T (2018) Targets of Neuroprotection in Glaucoma. J Ocu Pharmacol Ther 34:85–106. https://doi.org/10.1089/jop.2017.0041

    Article  CAS  Google Scholar 

  7. Francois M, Donovan P, Fontaine F (2020) Modulating transcription factor activity: Interfering with protein-protein interaction networks. Sem Cell Dev Biol 99:12–19. https://doi.org/10.1016/j.semcdb.2018.07.019

    Article  CAS  Google Scholar 

  8. Feng J, Xu J (2019) Identification of pathogenic genes and transcription factors in glaucoma. Mol Med Rep 20:216–224. https://doi.org/10.3892/mmr.2019.10236

    Article  PubMed  CAS  Google Scholar 

  9. Lee MY, Lu A, Gudas LJ (2010) Transcriptional regulation of Rex1 (zfp42) in normal prostate epithelial cells and prostate cancer cells. J Cell Physiol 224:17–27. https://doi.org/10.1002/jcp.22071

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kristensen DM, Nielsen JE, Skakkebaek NE, Graem N, Jacobsen GK, Rajpert-De Meyts E, Leffers H (2008) Presumed pluripotency markers UTF-1 and REX-1 are expressed in human adult testes and germ cell neoplasms. Hum Reprod 23:775–782. https://doi.org/10.1093/humrep/den010

    Article  PubMed  CAS  Google Scholar 

  11. Kristensen DM, Nielsen JE, Kalisz M, Dalgaard MD, Audouze K, Larsen ME, Jacobsen GK, Horn T, Brunak S, Skakkebaek NE, Leffers H (2010) OCT4 and downstream factors are expressed in human somatic urogenital epithelia and in culture of epididymal spheres. Mol Hum Reprod 16:835–845. https://doi.org/10.1093/molehr/gaq008

    Article  PubMed  CAS  Google Scholar 

  12. Rezende NC, Lee MY, Monette S, Mark W, Lu A, Gudas LJ (2011) Rex1 (Zfp42) null mice show impaired testicular function, abnormal testis morphology, and aberrant gene expression. Dev Biol 356:370–382. https://doi.org/10.1016/j.ydbio.2011.05.664

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Matenia D, Mandelkow EM (2009) The tau of MARK: a polarized view of the cytoskeleton. Trends Biochem Sci 34:332–342. https://doi.org/10.1016/j.tibs.2009.03.008

    Article  PubMed  CAS  Google Scholar 

  14. Lee S, Wang JW, Yu W, Lu B (2012) Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Abeta toxicity in Drosophila. Nat Commun 3:1312. https://doi.org/10.1038/ncomms2278

    Article  PubMed  CAS  Google Scholar 

  15. DiBona VL, Zhu W, Shah MK, Rafalia A, Ben Cheikh H, Crockett DP, Zhang H (2019) Loss of Par1b/MARK2 primes microglia during brain development and enhances their sensitivity to injury. J Neuroinflammation 16:11. https://doi.org/10.1186/s12974-018-1390-3

    Article  PubMed  PubMed Central  Google Scholar 

  16. Rohatgi T, Sedehizade F, Sabel BA, Reiser G (2003) Protease-activated receptor subtype expression in developing eye and adult retina of the rat after optic nerve crush. J Neuroscie Res 73:246–254. https://doi.org/10.1002/jnr.10643

    Article  CAS  Google Scholar 

  17. Langfelder P, Horvath S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9:559. https://doi.org/10.1186/1471-2105-9-559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Choi H, Choi SJ (2012) Detection of Edwardsiella tarda by fluorometric or biosensor methods using a peptide ligand. Anal Biochem 421:152–157. https://doi.org/10.1016/j.ab.2011.11.012

    Article  PubMed  CAS  Google Scholar 

  19. Wilson AM, Di Polo A (2012) Gene therapy for retinal ganglion cell neuroprotection in glaucoma. Gene Ther 19:127–136. https://doi.org/10.1038/gt.2011.142

    Article  PubMed  CAS  Google Scholar 

  20. You Y, Gupta VK, Li JC, Klistorner A, Graham SL (2013) Optic neuropathies: characteristic features and mechanisms of retinal ganglion cell loss. Rev Neuroscie 24:301–321. https://doi.org/10.1515/revneuro-2013-0003

    Article  Google Scholar 

  21. Wu Y, Zang WD, Jiang W (2014) Functional analysis of differentially expressed genes associated with glaucoma from DNA microarray data. Genet Mol Res 13:9421–9428. https://doi.org/10.4238/2014.November.11.7

    Article  PubMed  CAS  Google Scholar 

  22. Yan X, Yuan F, Chen X, Dong C (2015) Bioinformatics analysis to identify the differentially expressed genes of glaucoma. Mol Med Rep 12:4829–4836. https://doi.org/10.3892/mmr.2015.4030

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Bosze B, Moon MS, Kageyama R, Brown NL (2020) Simultaneous requirements for Hes1 in retinal neurogenesis and optic cup-stalk boundary Maintenance. J Neurosci 40:1501–1513. https://doi.org/10.1523/JNEUROSCI.2327-19.2020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Takatsuka K, Hatakeyama J, Bessho Y, Kageyama R (2004) Roles of the bHLH gene Hes1 in retinal morphogenesis. Brain Res 1004:148–155. https://doi.org/10.1016/j.brainres.2004.01.045

    Article  PubMed  CAS  Google Scholar 

  25. Lewis CJ, Hedberg-Buenz A, DeLuca AP, Stone EM, Alward WLM, Fingert JH (2017) Primary congenital and developmental glaucomas. Hum Mol Genet 26:R28–R36. https://doi.org/10.1093/hmg/ddx205

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Gualco G, Weiss LM, Bacchi CE (2010) MUM1/IRF4: a review. App Immunohistochem Mol Morphol 18:301–310. https://doi.org/10.1097/PAI.0b013e3181cf1126

    Article  CAS  Google Scholar 

  27. Yu CR, Choi JK, Uche AN, Egwuagu CE (2018) Production of IL-35 by Bregs is mediated through binding of BATF-IRF-4-IRF-8 complex to il12a and ebi3 promoter elements. J Leukoc Biolo 104:1147–1157. https://doi.org/10.1002/JLB.3A0218-071RRR

    Article  CAS  Google Scholar 

  28. Laino AM, Berry EG, Jagirdar K, Lee KJ, Duffy DL, Soyer HP, Sturm RA (2018) Iris pigmented lesions as a marker of cutaneous melanoma risk: an Australian case-control study. Br J Dermatol 178:1119–1127. https://doi.org/10.1111/bjd.16323

    Article  PubMed  CAS  Google Scholar 

  29. Rani A, Greenlaw R, Runglall M, Jurcevic S, John S (2014) FRA2 is a STAT5 target gene regulated by IL-2 in human CD4 T cells. PLoS ONE 9:e90370. https://doi.org/10.1371/journal.pone.0090370

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Sarode P, Zheng X, Giotopoulou GA, Weigert A, Kuenne C, Gunther S, Friedrich A, Gattenlohner S, Stiewe T, Brune B, Grimminger F, Stathopoulos GT, Pullamsetti SS, Seeger W, Savai R (2020) Reprogramming of tumor-associated macrophages by targeting beta-catenin/FOSL2/ARID5A signaling: a potential treatment of lung cancer. Sci Adv 6:eaaz6105. https://doi.org/10.1126/sciadv.aaz6105

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Chen M, Huang B, Zhu L, Chen K, Liu M, Zhong C (2020) Structural and functional overview of TEAD4 in cancer biology. Onco Targets Ther 13:9865–9874. https://doi.org/10.2147/OTT.S266649

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Appukuttan B, McFarland TJ, Davies MH, Atchaneeyasakul LO, Zhang Y, Babra B, Pan Y, Rosenbaum JT, Acott T, Powers MR, Stout JT (2007) Identification of novel alternatively spliced isoforms of RTEF-1 within human ocular vascular endothelial cells and murine retina. Invest Ophthalmol Vis Sci 48:3775–3782. https://doi.org/10.1167/iovs.06-1172

    Article  PubMed  Google Scholar 

  33. Mongan NP, Martin KM, Gudas LJ (2006) The putative human stem cell marker, Rex-1 (Zfp42): structural classification and expression in normal human epithelial and carcinoma cell cultures. Mol Carcinog 45:887–900. https://doi.org/10.1002/mc.20186

    Article  PubMed  CAS  Google Scholar 

  34. Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A (2012) The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 31:152–181. https://doi.org/10.1016/j.preteyeres.2011.11.002

    Article  PubMed  CAS  Google Scholar 

  35. Kanamori A, Catrinescu MM, Kanamori N, Mears KA, Beaubien R, Levin LA (2010) Superoxide is an associated signal for apoptosis in axonal injury. Brain 133:2612–2625. https://doi.org/10.1093/brain/awq105

    Article  PubMed  PubMed Central  Google Scholar 

  36. Agrawal V, Johnson SA, Reing J, Zhang L, Tottey S, Wang G, Hirschi KK, Braunhut S, Gudas LJ, Badylak SF (2010) Epimorphic regeneration approach to tissue replacement in adult mammals. Proc Natl Acad Sci USA 107:3351–3355. https://doi.org/10.1073/pnas.0905851106

    Article  PubMed  Google Scholar 

  37. Wang G, Badylak SF, Heber-Katz E, Braunhut SJ, Gudas LJ (2010) The effects of DNA methyltransferase inhibitors and histone deacetylase inhibitors on digit regeneration in mice. Regen Med 5:201–220. https://doi.org/10.2217/rme.09.91

    Article  PubMed  CAS  Google Scholar 

  38. Luk ST, Ng KY, Zhou L, Tong M, Wong TL, Yu H, Lo CM, Man K, Guan XY, Lee TK, Ma S (2020) Deficiency in embryonic stem cell marker reduced expression 1 activates mitogen-activated protein kinase kinase 6-dependent p38 mitogen-activated protein kinase signaling to drive hepatocarcinogenesis. Hepatology 72:183–197. https://doi.org/10.1002/hep.31020

    Article  PubMed  CAS  Google Scholar 

  39. Kreutter G, Kassem M, El Habhab A, Baltzinger P, Abbas M, Boisrame-Helms J, Amoura L, Peluso J, Yver B, Fatiha Z, Ubeaud-Sequier G, Kessler L, Toti F (2017) Endothelial microparticles released by activated protein C protect beta cells through EPCR/PAR1 and annexin A1/FPR2 pathways in islets. J Cell Mol Med 21:2759–2772. https://doi.org/10.1111/jcmm.13191

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, 130042, Jilin, People’s Republic of China

    Yuan Yin, Shuai Wu & Shiwei Huang

  2. Department of Ophthalmology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People’s Republic of China

    Lingzhi Niu

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YY and SW designed the study. SW, LZN and SWH collated the data, carried out data analyses and produced the initial draft of the manuscript. YY and SWH contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Shiwei Huang.

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Yin, Y., Wu, S., Niu, L. et al. A ZFP42/MARK2 regulatory network reduces the damage of retinal ganglion cells in glaucoma: a study based on GEO dataset and in vitro experiments. Apoptosis 27, 1049–1059 (2022). https://doi.org/10.1007/s10495-022-01746-9

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