Mycobacterium tuberculosis methyltransferase perturbs host epigenetic programming to promote bacterial survival

Mycobacterium tuberculosis ( Mtb ) has evolved several mechanisms to counter host defense arsenal for its proliferation. We show that Mtb employs multi-pronged approach to modify host epigenetic machinery for its survival upon infection. It secretes methyltransferase (MTase) Rv2067c into macrophages, trimethylating K79 of histone H3 in non-nucleosomal context. Rv2067c downregulates host MTase DOT1L, decreasing its H3K79me3 mark added nucleosomally on pro-inflammatory response genes. Consequent inhibition of caspase8 dependent apoptosis and enhancement of RIPK3 mediated necrosis results in increased pathogenesis. In parallel, Rv2067c enhances the expression of SESTRIN3, NLRC3 and TMTC1 enabling the pathogen to overcome host inflammatory and oxidative response. We provide structural basis for differential methylation of H3 by Rv2067c and DOT1L. The structure of Rv2067c and DOT1L explain how their action on H3K79 is temporally and spatially separated enabling Rv2067c to effectively intercept the host epigenetic circuit and downstream signalling.