Medical Research

Fred Hutchinson Cancer Research Center

Christopher D. Johnston, Susan Bullman, Angela H. Ting
Seattle, WA
$1,000,000
December 2020

Bacterial restriction-modification (RM) systems function as a defense mechanism against invasive DNA molecules.  RM systems are ubiquitous in bacterial strains within the human microbiota and target specific DNA sequences for methylation or digestion.  RM systems are known to be governed by their sequence specificity, and in the laboratory, RM enzymes will indiscriminately act on human DNA at their respective motifs.  Yet, in humans, DNA methylation is primarily associated with much shorter CpG motifs.  Although an essential epigenetic modification in normal human development, methylation is grossly disrupted in all human cancers.  How such abnormality is established during cancer formation remains an unsolved mystery.  Investigators at the Fred Hutchinson Cancer Research Center and the Lerner Research Institute at the Cleveland Clinic suggest that bacterial RM systems of the microbiota can directly induce aberrant methylation states within the human genome, thus, initiating prevalent epigenetic aberrancies observed in a subset of cancers.  The invasive and intracellular pathogen Fusobacterium nucleatum is intimately associated with colorectal cancer (CRC), enriched in both tumors and associated metastases.  Using CRC as a model, the investigators seek to determine if there is clear in vivo evidence of microbial RM enzymes interacting with human DNA, and if so, experimentally delineate the underlying molecular mechanism of these host-microbiota interactions.

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