Transcriptional regulation of the human ferritin gene by coordinated regulation of Nrf2 and protein arginine methyltransferases PRMT1 and PRMT4

Antioxidant genes such as ferritin are transcriptionally activated in oxidative stress via the antioxidant responsive element (ARE), to which nuclear factor‐E2‐related factor 2 (Nrf2) binds and activates transcription. Histone modification plays a cooperative and essential role in transcriptional re...

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Bibliographic Details
Published in:The FASEB journal 2013-09, Vol.27 (9), p.3763-3774
Main Authors: Huang, Bo‐Wen, Ray, Paul D., Iwasaki, Kenta, Tsuji, Yoshiaki
Format: Article
Language:English
Subjects:
antioxidant
Antioxidants - metabolism
arsenic
Arsenic - toxicity
Cell Line
Cells, Cultured
Ferritins - genetics
Fibroblasts - cytology
Fibroblasts - metabolism
histone methylation
Histones - metabolism
Humans
Keratinocytes - cytology
Keratinocytes - metabolism
Methylation
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
oxidative stress
Oxidative Stress - drug effects
Oxidative Stress - genetics
Protein-Arginine N-Methyltransferases - genetics
Protein-Arginine N-Methyltransferases - metabolism
Repressor Proteins - genetics
Repressor Proteins - metabolism
Research Communications
Transcription, Genetic - drug effects
Transcription, Genetic - genetics
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Summary:Antioxidant genes such as ferritin are transcriptionally activated in oxidative stress via the antioxidant responsive element (ARE), to which nuclear factor‐E2‐related factor 2 (Nrf2) binds and activates transcription. Histone modification plays a cooperative and essential role in transcriptional regulation; however, its role in antioxidant gene transcription remains elusive. Arsenic exposure activated ferritin transcription via the ARE concomitant with increased methylation of histones H4Arg3 (H4R3) and H3Arg17 (H3R17). To test our hypothesis that histone H4R3 and H3R17 methylation regulates ferritin transcription, H4R3 and H3R17 protein arginine (R) methyltransferases 1 and 4 (PRMT1 and PRMT4) were investigated. Arsenic exposure of human HaCaT keratinocytes induced nuclear accumulation of PRMT1 and PRMT4, histone H4R3 and H3R17 methylation proximal to the ARE, but not to the non‐ARE regions of ferritin genes. PRMT1 or PRMT4 knockdown did not block Nrf2 nuclear accumulation but inhibited Nrf2 binding to the AREs by ~40% (P
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.12-226043