Sharma Garima, Upadhyay Sandeep, Srilalitha M, Nandicoori Vinay K, Khosla Sanjeev
Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad 500001, India Graduate Studies, Manipal University, Manipal 576104, India.
National Institute of Immunology, Delhi 110067, India.
Nucleic Acids Res. 2015 Apr 30;43(8):3922-37. doi: 10.1093/nar/gkv261. Epub 2015 Mar 30.
To effectively modulate the gene expression within an infected mammalian cell, the pathogen Mycobacterium tuberculosis would need to bring about epigenetic modifications at appropriate genomic loci. Working on this hypothesis, we show in this study that the mycobacterial protein Rv2966c is a 5-methylcytosine-specific DNA methyltransferase that is secreted out from the mycobacterium and gets localized to the nucleus in addition to the cytoplasm inside the host cell. Importantly, Rv2966c binds to specific DNA sequences, methylates cytosines predominantly in a non-CpG context and its methylation activity is positively influenced by phosphorylation. Interestingly, like the mammalian DNA methyltransferase, DNMT3L, Rv2966c can also interact with histone proteins. Ours is the first study that identifies a protein from a pathogenic bacteria with potential to influence host DNA methylation in a non-canonical manner providing the pathogen with a novel mechanism to alter the host epigenetic machinery. This contention is supported by repression of host genes upon M. tuberculosis infection correlated with Rv2966c binding and non-CpG methylation.
为了有效调节受感染哺乳动物细胞内的基因表达，病原体结核分枝杆菌需要在适当的基因组位点进行表观遗传修饰。基于这一假设开展研究，我们在本研究中表明，分枝杆菌蛋白Rv2966c是一种5-甲基胞嘧啶特异性DNA甲基转移酶，它从分枝杆菌分泌出来，除了定位于宿主细胞内的细胞质外，还定位于细胞核。重要的是，Rv2966c与特定的DNA序列结合，主要在非CpG背景下使胞嘧啶甲基化，其甲基化活性受到磷酸化的正向影响。有趣的是，与哺乳动物DNA甲基转移酶DNMT3L一样，Rv2966c也能与组蛋白相互作用。我们的研究首次鉴定出一种来自致病细菌的蛋白，它有可能以非经典方式影响宿主DNA甲基化，为病原体提供了一种改变宿主表观遗传机制的新机制。结核分枝杆菌感染后宿主基因的抑制与Rv2966c结合和非CpG甲基化相关，支持了这一观点。
