Histone modification crosstalk between host and pathogen.

Bacterial pathogens modulate host cell physiology by secreting effector proteins that rewire host signaling pathways. A subset of these effectors directly modify host chromatin to reprogram gene expression and promote infection. While these enzymes are thought to function autonomously, the extent to which the host epigenetic landscape regulates their activity remains largely unknown. RomA and its homolog LegAs4 are Set domain-containing lysine methyltransferases from SIGNIFICANCE: Bacterial pathogens reprogram host gene expression by delivering effector proteins that modify chromatin, but it is not known how the host epigenetic environment impacts effector function. Here, we show that the Legionella effector RomA senses and responds to the host's existing epigenetic landscape and is selectively active only in specific chromatin contexts through mechanisms resembling those used by eukaryotic chromatin regulators. Notably, we uncover that RomA utilizes cis-histone and trans-histone crosstalk mechanisms previously observed only in eukaryotic systems. These reveals an unexpected form of host-pathogen crosstalk in which bacterial effector activity can be constrained by host epigenetic modifications.