Epigenetic interaction of microbes with their mammalian hosts.

The interaction of microbiota with its host has the ability to alter the cellular functions of both, through several mechanisms. Recent work, from many laboratories including our own, has shown that epigenetic mechanisms play an important role in the alteration of these cellular functions. Epigenetics broadly refers to change in the phenotype without a corresponding change in the DNA sequence. This change is usually brought by epigenetic modifications of the DNA itself, the histone proteins associated with the DNA in the chromatin, non-coding RNA or the modifications of the transcribed RNA. These modifications, also known as epigenetic code, do not change the DNA sequence but alter the expression level of specific genes. Microorganisms seem to have learned how to modify the host epigenetic code and modulate the host transcriptome in their favour. In this review, we explore the literature that describes the epigenetic interaction of bacteria, fungi and viruses, with their mammalian hosts.

Cytosine methylation by DNMT2 facilitates stability and survival of HIV-1 RNA in the host cell during infection.

The enigmatic methyltransferase, DNMT2 (DNA methyltransferase 2), structurally resembles a DNA methyltransferase, but has been shown to be a tRNA methyltransferase targeting cytosine within a specific CpG in different tRNA molecules. We had previously shown that, during environmental stress conditions, DNMT2 is re-localized from the nucleus to the cytoplasmic stress granules (SGs) and is associated with RNA-processing proteins. In the present study, we show that DNMT2 binds and methylates various mRNA species in a sequence-independent manner and gets re-localized to SGs in a phosphorylation-dependent manner. Importantly, our results indicate that HIV-1 enhances its survivability in the host cell by utilizing this RNA methylation capability of DNMT2 to increase the stability of its own genome. Upon infection, DNMT2 re-localizes from the nucleus to the SGs and methylates HIV-1 RNA. This DNMT2-dependent methylation provided post-transcriptional stability to the HIV-1 RNA. Furthermore, DNMT2 overexpression increased the HIV-1 viral titre. This would suggest that HIV hijacks the RNA-processing machinery within the SGs to ensure its own survival in the host cell. Thus, our findings provide for a novel mechanism by which virus tries to modulate the host cell machinery to its own advantage.

The DNA methyltranferase Dnmt2 participates in RNA processing during cellular stress.

The strong evolutionary conservation of the DNA methyltransferase, Dnmt2, is at odds with the absence of phenotypic defects in organisms lacking Dnmt2. The cellular processes where Dnmt2 has a role to play also remain largely undiscovered. Here we show that Dnmt2 is a part of RNA processing machinery during cellular stress. In addition to interacting with proteins involved in RNA processing and cellular stress, Dnmt2 exhibits nucleo-cytoplasmic shuttling in response to cellular stress. Normally present in the nucleus, under conditions of stress, Dnmt2 relocalises to the cytoplasmic Stress Granules and RNA processing bodies. Surprisingly, for a DNA methyltransferase, knockout of which showed no phenotypic defects in several species, our results show that transient transfection of Dnmt2 in mammalian cells causes cell lethality. Interestingly, Dnmt2 overexpression altered the expression of several genes involved in viral infection. Taking into consideration its recently identified role in retrotransposon silencing, the role of Dnmt2 in stress granules could represent a primitive cellular defense mechanism against viral infection.