dBRWD3調控Polycomb group 基因突變導致之組織異常增生以及異位基因表現

Abstract

基因體裡攜帶著遺傳訊息，不同的細胞使用著基因體上不同區域的遺傳訊息，這些不同區域的遺傳訊息表現，對於決定細胞的型態是非常重要的，但調控基因體上基因靜默的機制對於細胞型態的決定，其重要性等同於決定基因表現的機制。每種細胞型態的維持有賴於一些特殊基因持續的保持沉默。在發育過程前後，其中一種常被使用來靜默基因表現的機制，是一群Polycomb group蛋白質。Polycomb group蛋白質利用使chromatin 結構變緊密的方式，來抑制基因的表現，反觀一旦缺乏Polycomb group蛋白質時，它們所在的區域上的基因會被活化，進而產生異位基因表現而混亂正常細胞型態的發展造成發育缺失。Polycomb group蛋白質除了有維持正常細胞型態功能，也影響著正常細胞生理功能如細胞週期的運作。假如這群有監督功能的Polycomb group蛋白質突變則可能造成致癌基因的異位表現。這些不正常的遺傳訊息會導致細胞如同具有幹細胞的特性般，不正常分裂形成具有轉移性的癌細胞。目前對於控制異位基因表現的分子機制了解的相當少，而令人好奇的是，相同的Polycomb group蛋白質突變對於原位基因跟異位基因表現調控機制有何不同？假如我們可以解開Polycomb group蛋白質突變時對異位基因表現的調控機制，而此機制不影響正常生理基因表現，這將有助於選擇性的抑制癌細胞生長而不傷及正常細胞生長。我們的研究發現 ，Polycomb group蛋白質突變所造成異位基因表現需要dBRWd3的幫助。一旦去除dBRWD3 就會抑制異位基因表現，進而抑制細胞異位增生。dBRWD3 其功能是負向調控HIRA/Yemanuclein (YEM) 所攜帶的histone variant H3.3組裝進入chromatin。我們研究發現比起原位基因表現, 異位基因的表現更需要dBRWD3嚴謹控制histone variant H3.3組裝進入chromatin。不管是去除dBRWD3 或增加H3.3組裝進入chromatin都能有效抑制Polycomb group蛋白質突變所造成的異位基因表現及異位細胞增生，但不影響原位基因表現，這樣的發現有助於癌症治療發展及應用。

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.