Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation.

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• The gene regulatory functions of PBRM1 in normal epithelial homeostasis before cancer initiation are not well understood.
• PBRM1 is frequently mutated in epithelial cancers, suggesting a critical role in these tissues.

Purpose of the Study:

• To investigate the cell-state-specific gene regulatory roles of PBRM1 in human skin epithelium.
• To elucidate the molecular mechanisms underlying PBRM1's function in maintaining epithelial progenitor populations and regulating differentiation.

Main Methods:

• Utilized human skin epithelium as a model system to study PBRM1.
• Performed targeted screens to identify PBRM1 interacting proteins.
• Investigated the role of SUMOylation in PBRM1 function.

Main Results:

• PBRM1 exhibits distinct gene regulatory functions in progenitor versus differentiated epithelial cells.
• In progenitors, PBRM1 represses differentiation; in differentiated cells, it acts as an activator.
• PIAS1 was identified as a key interacting protein that co-localizes with PBRM1 to repress differentiation genes in progenitors.
• PIAS1 chromatin binding decreases significantly during differentiation.
• SUMOylation of PBRM1 contributes to its repressive role in progenitor maintenance.

Conclusions:

• PBRM1's gene regulatory activity is cell-state-dependent, switching between repressor and activator roles.
• The protein interactome, particularly PIAS1, influences PBRM1's function.
• PBRM1's role in epithelial homeostasis is modulated by its interactions and post-translational modifications like SUMOylation, despite stable chromatin binding.