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Nov 1, 2013

Fungal Gene Switch Discovery May Open Door to New Antibiotics

  • Scientists at Oregon State University say they have discovered that one gene in a common fungus acts as a master regulator, and deleting it has provided access to a wealth of new compounds that have never before been studied. The researchers believe their finding may open the door to the identification of a range of new antibiotics.

    Their study (“The Fusarium graminearum Histone H3 K27 Methyltransferase KMT6 Regulates Development and Expression of Secondary Metabolite Gene Clusters”) has just been published in PLOS Genetics.

    The OSU team succeeded in flipping a genetic switch that had silenced more than 2,000 genes in Fusarium graminearum. Until now this had kept it from producing novel compounds that may have useful properties, particularly for use in medicine but also perhaps in agriculture, industry, or biofuel production, the group explains.

    “We found that regions with secondary metabolite clusters are enriched for trimethylated histone H3 lysine 27 (H3K27me3), a histone modification associated with gene silencing. To find functions for H3K27me3 we deleted the gene for the putative H3K27 methyltransferase, KMT6. The kmt6 mutant lacks H3K27me3,” wrote the investigators. “We show that absence of H3K27me3 allowed expression of an additional 14% of the genome, resulting in derepression of genes predominantly involved in secondary metabolite pathways and other species-specific functions, including putative secreted pathogenicity factors. Results from this study provide the framework for novel targeted strategies to control the ‘cryptic genome,’ specifically secondary metabolite expression.”

    “About a third of the genome of many fungi has always been silent in the laboratory,” notes Michael Freitag, Ph.D., an associate professor of biochemistry and biophysics in the OSU College of Science. “Many fungi have antibacterial properties. It was no accident that penicillin was discovered from a fungus, and the genes for these compounds are usually in the silent regions of genomes.”

    However, as Dr. Freitag pointed out, “What we haven't been able to do is turn on more of the genome of these fungi, see the full range of compounds that could be produced by expression of their genes. Our finding should open the door to the study of dozens of new compounds, and we’ll probably see some biochemistry we’ve never seen before.”

    The gene (kmt6) that was deleted in this case regulates the methylation of histones, the proteins around which DNA is wound, according to Dr. Freitag. Creating a mutant without this gene allowed new expression, or overexpression of about 25% of the genome of this fungus, and the formation of many secondary metabolites.

    kmt6 encodes a master regulator that affects the expression of hundreds of genetic pathways, researchers say. It's been conserved through millions of years, in life forms as diverse as plants, fungi, fruit flies, and humans.

    The discovery of new antibiotics is of increasing importance as bacteria, parasites, and fungi are becoming increasingly resistant to older drugs.

    “Our studies will open the door to future precise ‘epigenetic engineering’ of gene clusters that generate bioactive compounds, e.g. putative mycotoxins, antibiotics, and industrial feedstocks,” the researchers stated in the conclusion of their journal article.



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