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Mechanism underlying synergic activation of Tyrosinase promoter by MITF and IRF4

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Abstract
Background: The transcription factor interferon regulatory factor 4 (IRF4) was identified to be involved in human pigmentation by genome-wide association studies (GWASs). The rs12203592-[T/C], which is located in intron 4 of IRF4, shows the strongest link to these pigmentation phenotypes including freckling, sun sensitivity, eye and hair color. Previous studies indicated a functional cooperation of IRF4 with Microphthalmia-associated transcription factor (MITF), a causing gene of Waardenburg syndrome (WS), to synergistically trans-activate Tyrosinase (TYR). However, the underlying mechanism is still unknown. Methods: To investigate the importance of DNA binding in the synergic effect of IRF4. Reporter plasmids with mutant TYR promoters was generated to locate the IRF4 DNA binding sites in the Tyrosinase minimal promoter. By building MITF and IRF4 truncated mutations plasmids, the necessary regions of the synergy functions of these two proteins were also located. Results: The cooperative effect between MITF and IRF4 was specific for TYR promoter. The DNA-binding of IRF4 was critical for the synergic function. IRF4 DNA binding sites in TYR promoter were identified. The Trans-activation domains in IRF4 (aa134-207, aa300-420) were both important for the synergic function, whereas the auto-mask domain (aa207-300) appeared to mask the synergic effect. Mutational analysis in MITF indicated that both DNA-binding and transcriptional activation domains were both required for this synergic effect. Conclusions: Here we showed that IRF4 potently synergized with MITF to activate the TYR promoter, which was dependent on DNA binding of IRF4. The synergic domains in both IRF4 and MITF were identified by mutational analysis. This identification of IRF4 as a partner for MITF in regulation of TYR may provide an important molecular function for IRF4 in the genesis of melanocytes and the pathogenic mechanism in WS.
Keywords
MICROPHTHALMIA TRANSCRIPTION FACTOR, WAARDENBURG SYNDROME TYPE-2, GENETIC-DETERMINANTS, IN-VIVO, EXPRESSION, PIGMENTATION, MUTATIONS, EPITHELIUM, EUROPEANS, MELANOMA, MITF, IRF4, TYR, synergy effects, transcriptional activation

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Chicago
Song, Jian, Xueming Liu, Jiada Li, Huadie Liu, Zhen Peng, Yalan Liu, Lingyun Mei, et al. 2017. “Mechanism Underlying Synergic Activation of Tyrosinase Promoter by MITF and IRF4.” International Journal of Clinical and Experimental Medicine 10 (4): 6631–6639.
APA
Song, Jian, Liu, X., Li, J., Liu, H., Peng, Z., Liu, Y., Mei, L., et al. (2017). Mechanism underlying synergic activation of Tyrosinase promoter by MITF and IRF4. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, 10(4), 6631–6639.
Vancouver
1.
Song J, Liu X, Li J, Liu H, Peng Z, Liu Y, et al. Mechanism underlying synergic activation of Tyrosinase promoter by MITF and IRF4. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE. 2017;10(4):6631–9.
MLA
Song, Jian, Xueming Liu, Jiada Li, et al. “Mechanism Underlying Synergic Activation of Tyrosinase Promoter by MITF and IRF4.” INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE 10.4 (2017): 6631–6639. Print.
@article{8527523,
  abstract     = {Background: The transcription factor interferon regulatory factor 4 (IRF4) was identified to be involved in human pigmentation by genome-wide association studies (GWASs). The rs12203592-[T/C], which is located in intron 4 of IRF4, shows the strongest link to these pigmentation phenotypes including freckling, sun sensitivity, eye and hair color. Previous studies indicated a functional cooperation of IRF4 with Microphthalmia-associated transcription factor (MITF), a causing gene of Waardenburg syndrome (WS), to synergistically trans-activate Tyrosinase (TYR). However, the underlying mechanism is still unknown. Methods: To investigate the importance of DNA binding in the synergic effect of IRF4. Reporter plasmids with mutant TYR promoters was generated to locate the IRF4 DNA binding sites in the Tyrosinase minimal promoter. By building MITF and IRF4 truncated mutations plasmids, the necessary regions of the synergy functions of these two proteins were also located. Results: The cooperative effect between MITF and IRF4 was specific for TYR promoter. The DNA-binding of IRF4 was critical for the synergic function. IRF4 DNA binding sites in TYR promoter were identified. The Trans-activation domains in IRF4 (aa134-207, aa300-420) were both important for the synergic function, whereas the auto-mask domain (aa207-300) appeared to mask the synergic effect. Mutational analysis in MITF indicated that both DNA-binding and transcriptional activation domains were both required for this synergic effect. Conclusions: Here we showed that IRF4 potently synergized with MITF to activate the TYR promoter, which was dependent on DNA binding of IRF4. The synergic domains in both IRF4 and MITF were identified by mutational analysis. This identification of IRF4 as a partner for MITF in regulation of TYR may provide an important molecular function for IRF4 in the genesis of melanocytes and the pathogenic mechanism in WS.},
  author       = {Song, Jian and Liu, Xueming and Li, Jiada and Liu, Huadie and Peng, Zhen and Liu, Yalan and Mei, Lingyun and He, Chufeng and Cai, Xinzhang and Chen, Hongsheng and Vleminckx, Kris and Feng, Yong},
  issn         = {1940-5901},
  journal      = {INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE},
  keyword      = {MICROPHTHALMIA TRANSCRIPTION FACTOR,WAARDENBURG SYNDROME TYPE-2,GENETIC-DETERMINANTS,IN-VIVO,EXPRESSION,PIGMENTATION,MUTATIONS,EPITHELIUM,EUROPEANS,MELANOMA,MITF,IRF4,TYR,synergy effects,transcriptional activation},
  language     = {eng},
  number       = {4},
  pages        = {6631--6639},
  title        = {Mechanism underlying synergic activation of Tyrosinase promoter by MITF and IRF4},
  volume       = {10},
  year         = {2017},
}

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