DOI QR코드

DOI QR Code

The Suppression Effects of Fat Mass and Obesity Associated Gene on the Hair Follicle-Derived Neural Crest Stem Cells Differentiating into Melanocyte by N6-Methyladenosine Modifying Microphthalmia-Associated Transcription Factor

  • Zhiwei Shang (Department of Dermatology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology) ;
  • Haixia Feng (Department of Dermatology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology) ;
  • Liye Xia (Department of Dermatology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology)
  • Received : 2022.06.30
  • Accepted : 2022.11.15
  • Published : 2023.05.30

Abstract

Background and Objectives: Melanocyte (MC), derived from neural crest stem cell (NCSC), are involved in the production of melanin. The mechanism by which NCSC differentiates to MC remains unclear. N6-methyladenosine (m6A) modification was applied to discuss the potential mechanism. Methods and Results: NCSCs were isolated from hair follicles of rats, and were obtained for differentiation. Cell viability, tyrosinase secretion and activity, and transcription factors were combined to evaluated the MC differentiation. RT-qPCR was applied to determine mRNA levels, and western blot were used for protein expression detection. Total m6A level was measured using methylated RNA immunoprecipitation (MeRIP) assay, and RNA immunoprecipitation was used to access the protein binding relationship. In current work, NCSCs were successfully differentiated into MCs. Fat mass and obesity associated gene (FTO) was aberrant downregulated in MCs, and elevated FTO suppressed the differentiation progress of NCSCs into MCs. Furthermore, microphthalmia-associated transcription factor (Mitf), a key gene involved in MC synthesis, was enriched by FTO in a m6A modification manner and degraded by FTO. Meanwhile, the suppression functions of FTO in the differentiation of NCSCs into MCs were reversed by elevated Mitf. Conclusions: In short, FTO suppressed the differentiating ability of hair follicle-derived NCSCs into MCs by m6A modifying Mitf.

Keywords

References

  1. Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature 2007;445:843-850 
  2. Li M, Knapp SK, Iden S. Mechanisms of melanocyte polarity and differentiation: what can we learn from other neuroectoderm-derived lineages? Curr Opin Cell Biol 2020;67:99-108 
  3. Nishimura EK. Melanocyte stem cells: a melanocyte reservoir in hair follicles for hair and skin pigmentation. Pigment Cell Melanoma Res 2011;24:401-410 
  4. Mort RL, Jackson IJ, Patton EE. The melanocyte lineage in development and disease. Development 2015;142:620-632 Erratum in: Development 2015;142:1387 
  5. Le Douarin NM, Dupin E. The "beginnings" of the neural crest. Dev Biol 2018;444 Suppl 1:S3-S13 
  6. Goding CR, Arnheiter H. MITF-the first 25 years. Genes Dev 2019;33:983-1007 
  7. Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 2006;12:406-414 
  8. Murtas D, Pilloni L, Diana A, Casula L, Tomei S, Piras F, Ferreli C, Maxia C, Perra MT. Tyrosinase and nestin immunohistochemical expression in melanocytic nevi as a histopathologic pattern to trace melanocyte differentiation and nevogenesis. Histochem Cell Biol 2019;151:175-185 
  9. Wang Y, Lan Y, Yang X, Gu Y, Lu H. TGFβ2 upregulates tyrosinase activity through opsin-3 in human skin melanocytes in vitro. J Invest Dermatol 2021;141:2679-2689 
  10. Lee JY, Lee J, Min D, Kim J, Kim HJ, No KT. Tyrosinase-targeting gallacetophenone inhibits melanogenesis in melanocytes and human skin-equivalents. Int J Mol Sci 2020;21:3144 
  11. Ma S, Chen C, Ji X, Liu J, Zhou Q, Wang G, Yuan W, Kan Q, Sun Z. The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol 2019;12:121 
  12. Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, Shi H, Skibbe J, Shen C, Hu C, Sheng Y, Wang Y, Wunderlich M, Zhang B, Dore LC, Su R, Deng X, Ferchen K, Li C, Sun M, Lu Z, Jiang X, Marcucci G, Mulloy JC, Yang J, Qian Z, Wei M, He C, Chen J. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification. Cell Stem Cell 2018;22:191-205.e9 
  13. Wen J, Lv R, Ma H, Shen H, He C, Wang J, Jiao F, Liu H, Yang P, Tan L, Lan F, Shi YG, He C, Shi Y, Diao J. Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal. Mol Cell 2018;69:1028-1038.e6 
  14. Lin J, Zhu Q, Huang J, Cai R, Kuang Y. Hypoxia promotes vascular smooth muscle cell (VSMC) differentiation of adipose-derived stem cell (ADSC) by regulating Mettl3 and paracrine factors. Stem Cells Int 2020;2020:2830565 
  15. Vasyliev RG, Gubar OS, Gordiienko IM, Litvinova LS, Rodnichenko AE, Shupletsova VV, Zlatska AV, Yurova KA, Todosenko NM, Khadzhynova VE, Shulha MV, Novikova SN, Zubov DO. Comparative analysis of biological properties of large-scale expanded adult neural crest-derived stem cells isolated from human hair follicle and skin dermis. Stem Cells Int 2019;2019:9640790 
  16. Ni Y, Zhang K, Liu X, Yang T, Wang B, Fu L, A L, Zhou Y. miR-21 promotes the differentiation of hair follicle-derived neural crest stem cells into Schwann cells. Neural Regen Res 2014;9:828-836 
  17. Dong D, Jiang M, Xu X, Guan M, Wu J, Chen Q, Xiang L. The effects of NB-UVB on the hair follicle-derived neural crest stem cells differentiating into melanocyte lineage in vitro. J Dermatol Sci 2012;66:20-28 
  18. Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M, Busch H, Boettcher M, Mougiakakos D, Reichardt W, Bronsert P, Brunton VG, Pilarsky C, Winkler TH, Brabletz S, Stemmler MP, Brabletz T. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 2017;19:518-529 
  19. Ohguchi K, Banno Y, Nakagawa Y, Akao Y, Nozawa Y. Negative regulation of melanogenesis by phospholipase D1 through mTOR/p70 S6 kinase 1 signaling in mouse B16 melanoma cells. J Cell Physiol 2005;205:444-451 
  20. Jin D, Guo J, Wu Y, Du J, Yang L, Wang X, Di W, Hu B, An J, Kong L, Pan L, Su G. m6 A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis. J Hematol Oncol 2019;12:135 Erratum in: J Hematol Oncol 2020;13:106 
  21. Dong G, Yu J, Shan G, Su L, Yu N, Yang S. N6-methyladenosine methyltransferase METTL3 promotes angiogenesis and atherosclerosis by upregulating the JAK2/STAT3 pathway via m6A reader IGF2BP1. Front Cell Dev Biol 2021;9:731810 
  22. Zhou S, Zeng H, Huang J, Lei L, Tong X, Li S, Zhou Y, Guo H, Khan M, Luo L, Xiao R, Chen J, Zeng Q. Epigenetic regulation of melanogenesis. Ageing Res Rev 2021;69:101349 
  23. Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a dynamic miniorgan. Curr Biol 2009;19:R132-R142 
  24. Lee J, Boscke R, Tang PC, Hartman BH, Heller S, Koehler KR. Hair follicle development in mouse pluripotent stem cell-derived skin organoids. Cell Rep 2018;22:242-254 
  25. Narytnyk A, Verdon B, Loughney A, Sweeney M, Clewes O, Taggart MJ, Sieber-Blum M. Differentiation of human epidermal neural crest stem cells (hEPI-NCSC) into virtually homogenous populations of dopaminergic neurons. Stem Cell Rev Rep 2014;10:316-326 
  26. Wilson R, Ahmmed AA, Poll A, Sakaue M, Laude A, Sieber-Blum M. Human peptidergic nociceptive sensory neurons generated from human epidermal neural crest stem cells (hEPI-NCSC). PLoS One 2018;13:e0199996 
  27. Dong D, Chen S, Feng C, Xiong H, Xu X. NB-UVB induces melanocytic differentiation of human hair follicle neural crest stem cells. Ann Dermatol 2020;32:289-297 
  28. Li J, Zhu L, Shi Y, Liu J, Lin L, Chen X. m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation. Am J Transl Res 2019;11:6084-6092 
  29. Tao L, Mu X, Chen H, Jin D, Zhang R, Zhao Y, Fan J, Cao M, Zhou Z. FTO modifies the m6A level of MALAT and promotes bladder cancer progression. Clin Transl Med 2021;11:e310 
  30. Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, Yang C, Chen Y. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther 2021;6:74 
  31. Shen GS, Zhou HB, Zhang H, Chen B, Liu ZP, Yuan Y, Zhou XZ, Xu YJ. The GDF11-FTO-PPARγ axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis. Biochim Biophys Acta Mol Basis Dis 2018;1864:3644-3654 
  32. Li L, Zang L, Zhang F, Chen J, Shen H, Shu L, Liang F, Feng C, Chen D, Tao H, Xu T, Li Z, Kang Y, Wu H, Tang L, Zhang P, Jin P, Shu Q, Li X. Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 2017;26:2398-2411 
  33. Cao Y, Zhuang Y, Chen J, Xu W, Shou Y, Huang X, Shu Q, Li X. Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice. Hum Mol Genet 2020;29:727-735