Synthetic Transcription Factors that Bind Modified Histones
Chromatin is a dynamic network of interacting proteins, DNA and RNA which regulates gene transcription and coordinates expression profiles in cells. Posttranslational modifications (PTMs) of histones within subunits of chromatin play a central role in the epigenetic regulation of genes that are implicated in cancer formation and cell differentiation.
Over the past decade, there have been several breakthroughs that have identified genes that are silenced in a variety of cancers compared to healthy cells. These genes when active, help prevent the formation and spread of tumors. Silencing of the genes is caused by an overabundance of repressive proteins that pack the genes into a repressed state. New inhibitor drugs targeting these repressive proteins have recently been developed. However, these inhibitors do not actively recruit the necessary transcriptional machinery, thus activation is only partial or temporary. Further, normal and mutant proteins that are not blocked by the drug can reinforce the silenced state. Some of these repressor protein inhibitors have off-target effects which is a roadblock for cancer research and drug development.
Researchers at Arizona State University have developed a novel approach and custom Polycomb-based Transcription factor (PcTFs) proteins that physically bind to and bridge PTM histones with endogenous transcription factors to reactivate silenced genes or repress the expression of certain genes. Modulating transcription of such genes, some of which encode tumor suppressors and developmental regulators, counteracts epigenetic states in cancer cells. These custom engineered proteins were shown to bind to histone H3 trimethylated at lysine 27 (H3K27me3), which is a histone methylation silencing marker, and directly stimulate activation of H3K27me3-repressed genes. Additionally, through analysis of gene expression in three distinct cancer cell lines, researchers identified a core set of 19 genes that were repressed. Researchers further showed that these genes can be activated by expressing the engineered PcTF proteins in the cells.
The custom proteins and novel approach have important implications for building and tuning fusion proteins that target sites of Polycomb-mediated silencing, which plays a central role in cancer and stem cell plasticity.
• Anti-cancer therapeutics
• Stem cell differentiation
• Tissue regeneration
• Production of biologicals
Benefits and Advantages
• Engages with histones instead of directly binding with DNA sequences
• Can mediate a gain-of-function epigenetic manipulation instead of a loss-of-function
• Enhanced binding affinity
• The histone targets have no known drug-resistant, viable mutants
• The custom proteins show enhanced activation and gene regulation
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CategoriesCancer Therapeutics Life Science (All LS Techs) Non-Cancer Therapeutics Proteomic Assays/Reagents/Tools Pharmaceuticals
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- Jovan Heusser