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Jan 31, 2014

Install Epigenetic Switches to Give Silent Genes a Voice

  • Which genes remain silent and which contribute full-throatedly to the transcriptional choir is conducted by means of epigenetic regulation, a remarkably precise system that keeps cells in tune and on tempo. But if the system falters, dissonances may arise, which is to say that diseases may result. But what if it were possible to intervene—to pick up the epigenetic baton, as it were—and restore transcriptional balance?

    One way of doing so is to effectively install artificial epigenetic switches. In fact, a kind of switch based on SAHA-PIP technology has shown promise by targeting specific regions of the genome and activating silent genes.

    PIPs, pyrrole-imidazole polyamides, are pseudopeptides that have been developed from the DNA-binding antibiotics distamycin A and netropsin. PIPs have interested researchers because they may be “tuned,” designed to bind to DNA in a sequence-specific manner. In fact, researchers from the Institute of Integrated Cell-Material Sciences (iCeMS) at Kyoto University have combined PIPs with SAHA, an epigenetic drug that switches genes to the “on” state.

    Specifically, SAHA is a histone deacetylase inhibitor. While SAHA is epigenetically active, it would be most useful if it could be directed to specific parts of the genome. That’s where PIPs—or, rather, SAHA-PIP conjugates—come in.

    “The PIPs serve as homing devices for SAHA to be more effective,” notes Junichi Taniguchi, part of the iCeMS research team. “Best of all, they are tunable, meaning that we can tinker with them to change their targets.”

    The iCeMS team, which was led by Namasivayam Ganesh Pandian, describes its latest work with SAHA-PIPs in the January 24 issue of Nature’s Scientific Reports, in an article entitled “Distinct DNA-based epigenetic switches trigger transcriptional activation of silent genes in human dermal fibroblasts.” The article shows how the authors used 32 different SAHA-PIPs to activate distinct and therapeutically important clusters of genes and noncoding RNAs.

    In the article, the authors describe how they relied on microarray studies and functional analysis to establish the selective gene-activating potential of SAHA-PIPs. In addition, they explain how they used qRT-PCR studies to validate the pattern observed with microarray analysis: “Some SAHA-PIPs activated therapeutically important genes including the recently identified KSR2, the obesity gene, and SEMA6A, the retinal ‘ON’ circuit factor.”

    The study’s principle investigator, Hiroshi Sugiyama, added this comment: “The hope is that we can one day harness the unique ability of these SAHA-PIPs to cure currently untreatable diseases where the switches for gene regulation have failed.”



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