Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Area of Science:

• Epigenetics
• Cell Death
• Cancer Biology

Background:

• Histone H2B monoubiquitination (H2Bub1) is linked to gene activation but its broader roles are unclear.
• Ferroptosis is iron-dependent cell death inhibited by SLC7A11 (xCT), a cystine-glutamate antiporter component.
• The involvement of nuclear events in ferroptosis regulation is largely unknown.

Purpose of the Study:

• To investigate the role of H2Bub1 in ferroptosis regulation.
• To elucidate the mechanism by which H2Bub1 influences ferroptosis.
• To determine the connection between p53, H2Bub1, and ferroptosis.

Main Methods:

• Analysis of H2Bub1 levels during erastin-induced ferroptosis.
• Assessing cellular sensitivity to ferroptosis upon H2Bub1 loss.
• Investigating H2Bub1's epigenetic regulation of SLC7A11 expression.
• Examining p53's effect on H2Bub1 levels and USP7 nuclear translocation.
• ChIP assays to determine p53-mediated H2Bub1 occupancy on the SLC7A11 gene.

Main Results:

• H2Bub1 levels decrease during erastin-induced ferroptosis, and H2Bub1 loss enhances ferroptosis sensitivity.
• H2Bub1 epigenetically activates SLC7A11 gene expression.
• p53 negatively regulates H2Bub1 levels independently of its transcriptional activity by promoting USP7 nuclear translocation.
• p53 represses SLC7A11 expression during erastin treatment by reducing H2Bub1 occupancy at the gene.

Conclusions:

• H2Bub1 plays a crucial role in regulating ferroptosis by controlling SLC7A11 expression.
• p53 utilizes a noncanonical chromatin regulatory mechanism involving H2Bub1 and USP7 to influence ferroptosis.
• This study reveals a novel H2Bub1-mediated epigenetic pathway linking p53 to ferroptosis regulation.