title: Mycoplasma CG- and GATC-specific DNA methyltransferases selectively and efficiently methylate the host genome and alter the epigenetic landscape in human cells.
abstract: Aberrant DNA methylation is frequently observed in disease, including many cancer types, yet the underlying mechanisms remain unclear. Because germline and somatic mutations in the genes that are responsible for DNA methylation are infrequent in malignancies, additional mechanisms must be considered. Mycoplasmas spp., including Mycoplasma hyorhinis, efficiently colonize human cells and may serve as a vehicle for delivery of enzymatically active microbial proteins into the intracellular milieu. Here, we performed, for the first time, genome-wide and individual gene mapping of methylation marks generated by the M. hyorhinis CG- and GATC-specific DNA cytosine methyltransferases (MTases) in human cells. Our results demonstrated that, upon expression in human cells, MTases readily translocated to the cell nucleus. In the nucleus, MTases selectively and efficiently methylated the host genome at the DNA sequence sites free from pre-existing endogenous methylation, including those in a variety of cancer-associated genes. We also established that mycoplasma is widespread in colorectal cancers, suggesting that either the infection contributed to malignancy onset or, alternatively, that tumors provide a favorable environment for mycoplasma growth. In the human genome, ∼ 11% of GATC sites overlap with CGs (e.g., CGAT(m)CG); therefore, the methylated status of these sites can be perpetuated by human DNMT1. Based on these results, we now suggest that the GATC-specific methylation represents a novel type of infection-specific epigenetic mark that originates in human cells with a previous exposure to infection. Overall, our findings unveil an entirely new panorama of interactions between the human microbiome and epigenome with a potential impact in disease etiology.
authors.affiliation: a Infectious & Inflammatory Disease Center ; Sanford-Burnham Medical Research Institute ; La Jolla , CA USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Chernov
authors.forename: Leticia
authors.initials: L
authors.lastname: Reyes
authors.forename: Zhenkang
authors.initials: Z
authors.lastname: Xu
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gonzalez
authors.forename: Georgiy
authors.initials: G
authors.lastname: Golovko
authors.forename: Scott
authors.initials: S
authors.lastname: Peterson
authors.forename: Manuel
authors.initials: M
authors.lastname: Perucho
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Fofanov
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D049109:Cell Proliferation; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D018899:CpG Islands; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005819:Genetic Markers; D015894:Genome, Human; D054884:Host-Pathogen Interactions; D006801:Humans / Q000469:parasitology; D008745:Methylation; D008969:Molecular Sequence Data; D009175:Mycoplasma Infections / Q000235:genetics; D045790:Mycoplasma hyorhinis / Q000502:physiology*
chemical_list: D005819:Genetic Markers; D015254:DNA Modification Methylases
keywords: 5-methylcytosine; CPGI; 5mC; CpG island; MTase; DNA methylation; DNA methyltransferases; Mycoplasma hyorhinis DNA cytosine methyltransferase.; colorectal cancer; epigenetics; host-pathogen interactions; mycoplasma