| Health / Medical Topics |
Gene Silencing Pathway
Packaging of DNA into chromatin allows the cell to store its genetic information efficiently and has an important role in regulating gene expression. Recent studies have revealed that chromatin structure can be altered by covalent modification of nucleosomes, in particular acetylation and methylation of the core histone tails. Histone hyperacetylation usually characterizes active chromatin, while histone deacetylation correlates with repressed transcription. The Polycomb group (PcG) proteins are constituents of evolutionary highly conserved molecular pathways regulating cell fate in several tissues through diverse mechanisms, including 1) regulation of self-renewal/proliferation, 2) regulation of senescence/immortalization, 3) interaction with the initiation transcription machinery, 4) interaction with chromatin-condensation proteins, 5) modification of histones, 6) inactivation of paternal X chromosome, and 7) regulation of cell death. The PcG proteins form multimeric protein complexes, PRC1 and PRC2 which are involved in the heritable, stable repression of genes through modification of chromatin structure. The EED-EZH2 complex (PRC 2 complex) acts early in development to set the stage for the long term repressive PRC1 complex. The PRC2 complex is probably tethered to promoters of affected genes through the interaction with specific DNA binding factors, such as YY1, a zinc finger transcription factor that acts as both a positive and negative regulator of transcription of cellular and viral genes. The EED-EZH2 proteins interact with histone deacetylase core complex consisting of the histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46. Histone deacetylation is probably a prerequisite for subsequent methylation, as histone tails cannot be acetylated and methylated in the same time. The PRC complex specifically methylates nucleosomal histone H3 at lysine 27, providing an epigenetic mark for binding of PRC1 complex. The histone methyltransferase activity of PRC2 is dependent on an intact SET domain in the EZH2 protein. PRC1 complex blocks chromatin remodeling by SWI/SNF factors, thus preventing transcription of repressed chromosome regions. (NCI Thesaurus/BIOCARTA)
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