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

• Published in: Cell genomics Vol. 4; no. 1; p. 100471
• Main Authors: Ho, Patric J., Kweon, Junghun, Blumensaadt, Laura A., Neely, Amy E., Kalika, Elizabeth, Leon, Daniel B., Oh, Sanghyon, Stringer, Cooper W.P., Lloyd, Sarah M., Ren, Ziyou, Bao, Xiaomin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.01.2024; Elsevier
• Subjects: BAF; differentiation; epidermis; epithelial; keratinocytes; PBRM1; PIAS1; progenitor; repression; skin; SUMO; SWI/SNF; PBRM1; SUMO; differentiation; BAF; SWI/SNF; skin; progenitor; epithelial; repression; keratinocytes; PIAS1; epidermis
• ISSN: 2666-979X; 2666-979X
• DOI: 10.1016/j.xgen.2023.100471

PBRM1 is frequently mutated in cancers of epithelial origin. How PBRM1 regulates normal epithelial homeostasis, prior to cancer initiation, remains unclear. Here, we show that PBRM1’s gene regulatory roles differ drastically between cell states, leveraging human skin epithelium (epidermis) as a research platform. In progenitors, PBRM1 predominantly functions to repress terminal differentiation to sustain progenitors’ regenerative potential; in the differentiation state, however, PBRM1 switches toward an activator. Between these two cell states, PBRM1 retains its genomic binding but associates with differential interacting proteins. Our targeted screen identified the E3 SUMO ligase PIAS1 as a key interactor. PIAS1 co-localizes with PBRM1 on chromatin to directly repress differentiation genes in progenitors, and PIAS1’s chromatin binding drastically diminishes in differentiation. Furthermore, SUMOylation contributes to PBRM1’s repressive function in progenitor maintenance. Thus, our findings highlight PBRM1’s cell-state-specific regulatory roles influenced by its protein interactome despite its stable chromatin binding. [Display omitted] •PBRM1 represses differentiation in progenitors but not in the differentiation state•PBRM1’s protein interactome, but not genomic binding, alters in cell-state switch•PIAS1 and PBRM1 co-localize on chromatin in progenitors but not in differentiation•SUMOylation contributes to PBRM1’s repressive function in progenitor maintenance Ho et al. demonstrate that PBRM1 switches from repressive to activating roles in differentiation gene regulation, as human skin epidermal cells transition from progenitor state to differentiation state. They identified that the changes in PBRM1’s interacting proteins such as PIAS1, but not PBRM1’s genomic binding, underlie this functional change.