dBRWD3 Regulates Tissue Overgrowth and Ectopic Gene Expression Caused by Polycomb Group Mutations
| العنوان: | dBRWD3 Regulates Tissue Overgrowth and Ectopic Gene Expression Caused by Polycomb Group Mutations |
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| المؤلفون: | Yu-Chen Tsai, Pang-Hung Hsu, Shih-Peng Chan, Zong-Siou Shih, Kuo-How Huang, Yi-Jyun Chen, June-Tai Wu, Kwei-Yan Liu, Wei-Yu Chen, Kuan-Lin Kuo, Hsiu-Hsiang Lee, Ya-Wen Liu, Paul-Chen Hsieh, Hsueh-Tzu Shih |
| المصدر: | PLoS Genetics, Vol 12, Iss 9, p e1006262 (2016) PLoS Genetics |
| بيانات النشر: | Public Library of Science (PLoS), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, genetic structures, Cellular differentiation, Polycomb-Group Proteins, Gene Expression, Cell Cycle Proteins, Eye, medicine.disease_cause, Biochemistry, Histones, Gene expression, Medicine and Health Sciences, Morphogenesis, Drosophila Proteins, Genetics (clinical), Regulator gene, Regulation of gene expression, Mutation, Cell Cycle, Gene Expression Regulation, Developmental, Nuclear Proteins, Cell Differentiation, Chromatin, Drosophila melanogaster, Imaginal Discs, Anatomy, Research Article, lcsh:QH426-470, DNA transcription, macromolecular substances, Cell fate determination, Biology, Research and Analysis Methods, 03 medical and health sciences, Ocular System, DNA-binding proteins, Genetics, Polycomb-group proteins, medicine, Animals, Histone Chaperones, Gene Regulation, Molecular Biology Techniques, Molecular Biology, Ecology, Evolution, Behavior and Systematics, fungi, Biology and Life Sciences, Proteins, body regions, lcsh:Genetics, 030104 developmental biology, Cancer research, Eyes, Ectopic expression, Head, Transcription Factors, Cloning, Developmental Biology |
| الوصف: | To maintain a particular cell fate, a unique set of genes should be expressed while another set is repressed. One way to repress gene expression is through Polycomb group (PcG) proteins that compact chromatin into a silent configuration. In addition to cell fate maintenance, PcG proteins also maintain normal cell physiology, for example cell cycle. In the absence of PcG, ectopic activation of the PcG-repressed genes leads to developmental defects and malignant tumors. Little is known about the molecular nature of ectopic gene expression; especially what differentiates expression of a given gene in the orthotopic tissue (orthotopic expression) and the ectopic expression of the same gene due to PcG mutations. Here we present that ectopic gene expression in PcG mutant cells specifically requires dBRWD3, a negative regulator of HIRA/Yemanuclein (YEM)-mediated histone variant H3.3 deposition. dBRWD3 mutations suppress both the ectopic gene expression and aberrant tissue overgrowth in PcG mutants through a YEM-dependent mechanism. Our findings identified dBRWD3 as a critical regulator that is uniquely required for ectopic gene expression and aberrant tissue overgrowth caused by PcG mutations. Author Summary Genetic information is stored in our genomic DNA, and different cells retrieve distinct sets of information from our genome. While it is important to activate genomic regions encoding proteins that are essential for a given cell type, it is equally important to silence genomic regions encoding proteins that are potentially harmful to this type of cells. One of the gene silencing mechanisms frequently used during and after development is mediated by the Polycomb group (PcG) proteins. If this guardian function does not perform correctly due to PcG mutations, genes that are normally silenced—such as oncogenes—are expressed aberrantly. Due to the activation of oncogenes and the loss of other PcG functions, PcG mutant cells often begin to display hallmarks of cancer, such as proliferating beyond control, acquiring stem-cell-like properties, and migrating to distant sites. If the transcriptional mechanisms underlying aberrant gene expression in PcG-mutant cancer cells differ from gene expression in normal cells, we may be able to selectively inhibit the growth of cancer cells without affecting their normal counterparts. Here we show that the difference between these two types of gene expression resides in their sensitivity to dBRWD3, a negative regulator of the deposition of histone H3 variant H3.3. Our results indicate that the inactivation of dBRWD3 or promotion of H3.3 deposition may selectively suppress ectopic gene expression and tumorigenesis driven by mutations in PcG. |
| اللغة: | English |
| تدمد: | 1553-7404 1553-7390 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4c93597cbd3a982741a6a858dc1a4aabTest http://europepmc.org/articles/PMC5010193?pdf=renderTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4c93597cbd3a982741a6a858dc1a4aab |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537404 15537390 |
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