Metabolic imprint of an intracellular pathogen drives histone hypermethylation and tunes the host transcriptional response to infection

Chlamydia trachomatis , an intracellular bacterium, highjacks metabolites from the host cell. We provide evidence of global hypermethylation of the host proteome, including histones, during the late stages of infection and that histone hypermethylation is the result of metabolic imbalance favoring the activity of lysine methyl transferases over demethylases. We find that histones hypermethylated at residues H3K4 and H3K9 are distributed throughout the chromatin. Inhibition of bacterial growth, or supplementation of the culture medium with iron or with dimethyl-ketoglutarate (DMKG) reduced histone hypermethylation. DMKG supplementation modified the transcription of about one third of the infection-responsive genes, including genes involved in the innate response to infection. Transfer RNA (tRNA) levels decreased late in infection and DMKG supplementation prevented this phenomenon. Finally, we uncovered a robust, histone demethylase dependent shut-down of the innate response in the mouse genital tract shortly after the acute phase of infection. Overall, our data show that the metabolic pressure exerted by a pathogen with an intracellular lifestyle drives an epigenetic imprint that tunes the transcriptional response of its host.