Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression
| Autor: | Jasbir Kaur, Bridget Matikainen, Gregory Moy, Ming-Ming Zhou, Patrizia Casaccia, Yoel Rodríguez, Lei Zeng, Guillermo Gerona-Navarro, Alexander N. Plotnikov, Adam Vincek, Mar Gacias, Guangtao Zhang, Elena Rusinova, Jennifer Joshua |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Transcription Genetic Clinical Biochemistry Biology 01 natural sciences Biochemistry Article Substrate Specificity Small Molecule Libraries Mice 03 medical and health sciences Transcription (biology) Gene expression Drug Discovery medicine Animals Humans Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences 010405 organic chemistry Cell growth Lysine Stem Cells Neurodegeneration Nuclear Proteins Acetylation Cell Differentiation General Medicine medicine.disease Oligodendrocyte 0104 chemical sciences Chromatin Cell biology Bromodomain Oligodendroglia medicine.anatomical_structure Molecular Medicine Transcription Factors |
| Zdroj: | Chemistry & Biology. 21(7):841-854 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2014.05.009 |
| Popis: | Lysine acetylation regulates gene expression through modulating protein-protein interactions in chromatin. Chemical inhibition of acetyl-lysine binding bromodomains of the major chromatin regulators BET (bromodomain and extra-terminal domain) proteins, has been shown to effectively block cell proliferation in cancer and inflammation. However, whether selective inhibition of individual BET bromodomains has distinctive functional consequences, remains only partially understood. In this study, we show that selective chemical inhibition of the first bromodomain of BET proteins using our newly designed small molecule inhibitor, Olinone, accelerated the progression of mouse primary oligodendrocyte progenitors towards differentiation, while inhibition of both bromodomains of BET proteins hindered differentiation. This effect was target-specific, as it was not detected in cells treated with inactive analogues and independent of any effect on proliferation. Therefore, selective chemical modulation of individual bromodomains, rather than use of broad-based inhibitors may enhance regenerative strategies in disorders characterized by myelin loss such as aging and neurodegeneration. |
| Databáze: | OpenAIRE |
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