Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation
Summary: 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)...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Cell Genomics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666979X23003154 |
| _version_ | 1797356855406624768 |
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| author | Patric J. Ho Junghun Kweon Laura A. Blumensaadt Amy E. Neely Elizabeth Kalika Daniel B. Leon Sanghyon Oh Cooper W.P. Stringer Sarah M. Lloyd Ziyou Ren Xiaomin Bao |
| author_facet | Patric J. Ho Junghun Kweon Laura A. Blumensaadt Amy E. Neely Elizabeth Kalika Daniel B. Leon Sanghyon Oh Cooper W.P. Stringer Sarah M. Lloyd Ziyou Ren Xiaomin Bao |
| author_sort | Patric J. Ho |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-08T14:34:44Z |
| format | Article |
| id | doaj.art-12d512de84b3471089ce2f5a0a891fa4 |
| institution | Directory Open Access Journal |
| issn | 2666-979X |
| language | English |
| last_indexed | 2024-03-08T14:34:44Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Genomics |
| spelling | doaj.art-12d512de84b3471089ce2f5a0a891fa42024-01-12T04:57:46ZengElsevierCell Genomics2666-979X2024-01-0141100471Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperationPatric J. Ho0Junghun Kweon1Laura A. Blumensaadt2Amy E. Neely3Elizabeth Kalika4Daniel B. Leon5Sanghyon Oh6Cooper W.P. Stringer7Sarah M. Lloyd8Ziyou Ren9Xiaomin Bao10Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USADepartment of Dermatology, Northwestern University, Chicago, IL 60611, USADepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA; Department of Dermatology, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666979X23003154BAFSWI/SNFPBRM1PIAS1SUMOprogenitor |
| spellingShingle | Patric J. Ho Junghun Kweon Laura A. Blumensaadt Amy E. Neely Elizabeth Kalika Daniel B. Leon Sanghyon Oh Cooper W.P. Stringer Sarah M. Lloyd Ziyou Ren Xiaomin Bao Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation Cell Genomics BAF SWI/SNF PBRM1 PIAS1 SUMO progenitor |
| title | Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation |
| title_full | Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation |
| title_fullStr | Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation |
| title_full_unstemmed | Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation |
| title_short | Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation |
| title_sort | multi omics integration identifies cell state specific repression by pbrm1 pias1 cooperation |
| topic | BAF SWI/SNF PBRM1 PIAS1 SUMO progenitor |
| url | http://www.sciencedirect.com/science/article/pii/S2666979X23003154 |
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