A biochemical screening platform to target chromatin states using condensates as a tool
Chromatin states define cell fates and consequently dysfunctional chromatin states drive disease. Conventional approaches to target dysfunctional chromatin states typically rely on targeting a defined, structured binding pocket of a specific chromatin protein. However, drugs developed from targeting...
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Elsevier
2025-06-01
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| Series: | SLAS Discovery |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2472555225000292 |
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| author | Laura J. Hsieh Tracy Lou Muryam A. Gourdet Emily Wong Geeta J. Narlikar |
| author_facet | Laura J. Hsieh Tracy Lou Muryam A. Gourdet Emily Wong Geeta J. Narlikar |
| author_sort | Laura J. Hsieh |
| collection | DOAJ |
| description | Chromatin states define cell fates and consequently dysfunctional chromatin states drive disease. Conventional approaches to target dysfunctional chromatin states typically rely on targeting a defined, structured binding pocket of a specific chromatin protein. However, drugs developed from targeting single chromatin proteins have often failed in the clinic due to toxicity from broad non-specific effects on the genome. Substantial previous work has indicated that the function of a given chromatin state is encoded in the context-dependent protein-protein interactions (PPIs) between the Intrinsically disordered regions (IDRs) and folded domains of the multiple constituents. Currently, there are no drug discovery approaches that target the complex multivalent protein interactions within a given dysfunctional chromatin state. Therefore, new methods are required to target chromatin within specific conformational contexts for better translation into humans. Prior discoveries from our group and others have shown that chromatin intrinsically forms condensates through weak, yet specific, multivalent interactions between itself and other components. Using this intrinsic property of chromatin, we have developed a new screening method to address this technology gap and identify modulators of dysfunctional chromatin states for drug discovery. Here, we show that we can recreate different chromatin contexts as phase-separated condensates that have distinct biochemical and biophysical properties. Furthermore, we have scaled the technology into a screening platform and identify small molecules that modulate chromatin states specifically based on their chromatin context. We anticipate that such specific targeting of a disease driving chromatin assembly would reduce off-target effects, translate better into humans and open a new landscape of therapeutic possibilities for targeting complex, multivalent interactions. |
| format | Article |
| id | doaj-art-e1b7e9e024874824a3f1a03d0843e86b |
| institution | Kabale University |
| issn | 2472-5552 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | SLAS Discovery |
| spelling | doaj-art-e1b7e9e024874824a3f1a03d0843e86b2025-08-20T03:49:03ZengElsevierSLAS Discovery2472-55522025-06-013310023610.1016/j.slasd.2025.100236A biochemical screening platform to target chromatin states using condensates as a toolLaura J. Hsieh0Tracy Lou1Muryam A. Gourdet2Emily Wong3Geeta J. Narlikar4Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; TippingPoint Biosciences, Inc., San Francisco, CA 94107, USA; Lead Contacts, USA; Corresponding author at: TippingPoint Biosciences, Inc., San Francisco, CA 94107, USA.Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USADepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; TippingPoint Biosciences, Inc., San Francisco, CA 94107, USADepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USADepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Lead Contacts, USA; Corresponding author at: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.Chromatin states define cell fates and consequently dysfunctional chromatin states drive disease. Conventional approaches to target dysfunctional chromatin states typically rely on targeting a defined, structured binding pocket of a specific chromatin protein. However, drugs developed from targeting single chromatin proteins have often failed in the clinic due to toxicity from broad non-specific effects on the genome. Substantial previous work has indicated that the function of a given chromatin state is encoded in the context-dependent protein-protein interactions (PPIs) between the Intrinsically disordered regions (IDRs) and folded domains of the multiple constituents. Currently, there are no drug discovery approaches that target the complex multivalent protein interactions within a given dysfunctional chromatin state. Therefore, new methods are required to target chromatin within specific conformational contexts for better translation into humans. Prior discoveries from our group and others have shown that chromatin intrinsically forms condensates through weak, yet specific, multivalent interactions between itself and other components. Using this intrinsic property of chromatin, we have developed a new screening method to address this technology gap and identify modulators of dysfunctional chromatin states for drug discovery. Here, we show that we can recreate different chromatin contexts as phase-separated condensates that have distinct biochemical and biophysical properties. Furthermore, we have scaled the technology into a screening platform and identify small molecules that modulate chromatin states specifically based on their chromatin context. We anticipate that such specific targeting of a disease driving chromatin assembly would reduce off-target effects, translate better into humans and open a new landscape of therapeutic possibilities for targeting complex, multivalent interactions.http://www.sciencedirect.com/science/article/pii/S2472555225000292ChromatinCondensatesPPIsIDRs |
| spellingShingle | Laura J. Hsieh Tracy Lou Muryam A. Gourdet Emily Wong Geeta J. Narlikar A biochemical screening platform to target chromatin states using condensates as a tool SLAS Discovery Chromatin Condensates PPIs IDRs |
| title | A biochemical screening platform to target chromatin states using condensates as a tool |
| title_full | A biochemical screening platform to target chromatin states using condensates as a tool |
| title_fullStr | A biochemical screening platform to target chromatin states using condensates as a tool |
| title_full_unstemmed | A biochemical screening platform to target chromatin states using condensates as a tool |
| title_short | A biochemical screening platform to target chromatin states using condensates as a tool |
| title_sort | biochemical screening platform to target chromatin states using condensates as a tool |
| topic | Chromatin Condensates PPIs IDRs |
| url | http://www.sciencedirect.com/science/article/pii/S2472555225000292 |
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