Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non‐apoptotic cell death characterized by the iron‐dependent overproduction of li...

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Published in:EMBO reports 2019-07, Vol.20 (7), p.e47563-n/a
Main Authors: Wang, Yufei, Yang, Lu, Zhang, Xiaojun, Cui, Wen, Liu, Yanping, Sun, Qin‐Ru, He, Qing, Zhao, Shiyan, Zhang, Guo‐An, Wang, Yequan, Chen, Su
Format: Article
Language:English
Subjects:
Antioxidants
Apoptosis
Cell death
Chromatin
Cystine
Epigenetics
Ferroptosis
Gene expression
Gene silencing
H2B monoubiquitination
Histone H2B
Iron
Lipid peroxidation
Lipids
Lysine
Nuclear transport
Occupancy
p53
p53 Protein
Regulatory mechanisms (biology)
SCL7A11
Sensitivity
Transcription activation
Transcription factors
Translocation
Tumor suppressor genes
Ubiquitination
USP7
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Summary:Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non‐apoptotic cell death characterized by the iron‐dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin‐induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1‐mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis. Synopsis This study uncovers a previously unknown epigenetic regulatory mechanism for the control of ferroptosis by p53‐USP7‐H2Bub1 axis. H2Bub1 is a novel epigenetic regulator of ferroptosis. p53 regulates H2Bub1 independent of its transcription factor activity by recruiting the H2Bub1 deubiquitinase USP7 to chromatin. p53‐USP7 interplay reduces the occupancy of H2Bub1 on the SLC7A11 regulatory region, resulting in transcriptional repression and increased sensitivity to ferroptosis induction. These results not only suggest a novel role of H2Bub1 in the regulation of ferroptosis but also reveal a relative direct role of p53 in the regulation of chromatin events. p53 recruits USP7 to the regulatory region of SLC7A11 to reduce H2B monoubiquitination, resulting in transcriptional repression of SCL7A11 and ferroptosis induction. These results uncover an epigenetic regulatory mechanism for the control of ferroptosis.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.201847563