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  4. dBRWD3 regulates tissue overgrowth and ectopic gene expression caused by Polycomb group mutations
 
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dBRWD3 regulates tissue overgrowth and ectopic gene expression caused by Polycomb group mutations

Date Issued
2016
Date
2016
Author(s)
Shih, Hsueh-Tzu
DOI
10.6342/NTU201602496
URI
http://ntur.lib.ntu.edu.tw//handle/246246/271716
Abstract
Genetic information is stored in our genomic DNA. Different cells use different sets of information stored at the different genomic regions. 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. To maintain a cell fate, a unique set of genes must be repressed. One of the gene silencing mechanisms frequently used during and after development is Polycomb group (PcG) proteins. PcG proteins compact chromatin into a silent configuration and thus repress gene expression. In the absence of PcG, ectopic activation of the PcG-repressed genes leads to cell fate changes and thereby developmental defects. In addition to cell fate maintenance, PcG proteins also maintain normal cell physiology, for example cell cycle. If this guardian function performs incorrectly due to mutations in PcG genes, the otherwise silenced genes (e.g., oncogenes) express ectopically. As a result, the released information guides cells to proliferate beyond control, acquire stem cell-like properties, and migrate to distant sites- hallmarks of cancers. 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. If we can decipher the transcriptional regulations that are specific to ectopic expression of oncogenes in cancer cells lacking PcG, we may be able to selectively inhibit the growth of cancer cells without affecting normal cells. 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 in a YEM-dependent mechanism. The difference between ectopic and orthotopic gene expression resides in their sensitivity to dBRWD3. Our results indicate that the inactivation of dBRWD3 or promotion of H3.3 deposition may selectively suppress the PcG mutation-driven ectopic gene expression and tumorigenesis.
Subjects
dBRWD3
Polycomb group (PcG) proteins
tissue overgrowth
ectopic gene expression
SDGs

[SDGs]SDG3

Type
thesis
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ntu-105-D98448007-1.pdf

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23.32 KB

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Adobe PDF

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(MD5):becccb8e1f6ece8468c176fb099fc8da

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