Pan-SMARCA/PB1 Bromodomain Inhibitors and Their Role in Regulating Adipogenesis
| Autor: | Andreas C. Joerger, Xiaomin Ni, Sebastian Mathea, Andreas Krämer, Stefan Knapp, Marek Wanior, David Heidenreich, Tamara Göbel, Svenja Simonyi, Franziska Preuss, Astrid S. Kahnt |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
cells
Cellular differentiation genetic processes macromolecular substances 01 natural sciences Chromatin remodeling Mice 03 medical and health sciences Protein Domains 3T3-L1 Cells Cell Line Tumor Drug Discovery Animals Humans Amino Acid Sequence Peptide sequence Transcription factor Cell Proliferation 030304 developmental biology 0303 health sciences Adipogenesis Chemistry Cell Differentiation 0104 chemical sciences Cell biology Bromodomain DNA-Binding Proteins Pyridazines enzymes and coenzymes (carbohydrates) 010404 medicinal & biomolecular chemistry Cell culture SMARCA4 Molecular Medicine biological phenomena cell phenomena and immunity Transcription Factors |
| Zdroj: | Journal of Medicinal Chemistry. 63:14680-14699 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Accessibility of the human genome is modulated by the ATP-driven SWI/SNF chromatin remodeling multiprotein complexes BAF (BRG1/BRM-associated factor) and PBAF (polybromo-associated BAF factor), which involves reading of acetylated histone tails by the bromodomain-containing proteins SMARCA2 (BRM), SMARCA4 (BRG1), and polybromo-1. Dysregulation of chromatin remodeling leads to aberrant cell proliferation and differentiation. Here, we have characterized a set of potent and cell-active bromodomain inhibitors with pan-selectivity for canonical family VIII bromodomains. Targeted SWI/SNF bromodomain inhibition blocked the expression of key genes during adipogenesis, including the transcription factors PPARγ and C/EBPα, and impaired the differentiation of 3T3-L1 murine fibroblasts into adipocytes. Our data highlight the role of SWI/SNF bromodomains in adipogenesis and provide a framework for the development of SWI/SNF bromodomain inhibitors for indirect targeting of key transcription factors regulating cell differentiation. |
| Databáze: | OpenAIRE |
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