Behind the scenes: Enigma of epigenetics


Breaking down the microbiology world one bite at a time

Behind the scenes: Enigma of epigenetics

Suppose that a bacterium’s life is a movie. Now, imagine the cast of that movie is represented by different genes of the bacterial genome. Wait a minute… Where is the director? How can a movie be made without one? Here comes someone called “epigenetics” and says: “Don’t worry! I am here to the rescue!”

For a long time, bacterial genome content has been considered as the protagonist of the mysterious mechanisms of microbial life. Yet, parts of these genomes remained inexplicable to scientists for decades. This hidden entity, also known as epigenetics, describes how environmental factors influence the  genes of a microorganism. 

In bacteria, epigenetics moderates the gene expression. The idea behind this phenomenon comes from another system called Restriction-Modification (RM) system, which acts as a safety mechanism. This system is used in situations when foreign DNA sequences attack the bacterial genome. For instance, this could happen in the process of horizontal gene transfer (HGT), where bacteria accidentally acquire genes with no apparent function or genes which can shorten a bacterium’s life. The RM system protects bacterial genomes from such foreign gene sequences and reduces the frequency of horizontal gene transfer.

The RM system consists of two enzymes: restriction enzyme and DNA methyltransferase. Restriction enzyme breaks foreign DNA, and DNA methyltransferase protects the bacterial cellular DNA from destruction, while leaving the foreign DNA non-methylated. As a result, the restriction enzyme cuts the exposed foreign DNA into small pieces, making it impossible to be incorporated into the bacterial genome.

The methyltransferase enzymes are usually specific to an RM system and hence, have a defined function in bacteria. However, some enzymes do not belong to an RM system and act on their own. These are known as orphan methyltransferases. Such enzymes methylate bacterial DNA at random locations. These methylated locations indirectly affect the surrounding genes, and, hence, lead to a modified protein coded by those genes. This, in turn, affects the growth of bacteria.

Sequencing the mystery

Commonly used techniques for the detection of methylated bases, such as bisulphite sequencing, can usually miss bits of DNA modified by orphan enzymes. These techniques require prior knowledge of methylated sequences, like the position in the sequence at which methylation is expected. However, third-generation sequencing techniques have revolutionized the world of bacterial epigenetics. They do not require manipulations of the genome to detect methylated sites. In addition, these techniques record signal-specific information for each modified position accurately. Such techniques, hence, solved the issues related to DNA methylation detection.

Did you know that epigenetic changes make bacteria a ‘jack of all trades’?

Many of the epigenetic changes lead to phase variation in bacteria. Phase variation refers to random switching on and off of gene expression, just like an electric switch controlling the electricity of your room. Each of these changes occur during a cycle of genome replication, and this makes the on/off switch unpredictable for researchers to register. For instance, in Salmonella, the movement through flagella (the tentacle-like arms all over the body of the bacteria) is controlled by such phase variations. This enables co-existence of two types of the same Salmonella strain! 

Figure 1: Subpopulations of same Salmonella strain can co-exist in gut environment

Now, you will ask, how does this help Salmonella? Well, once Salmonella has both with-flagella and without-flagella populations (Figu, the bacteria can survive under multiple environment conditions:

a)     A stable nutritional environment provides a perfect opportunity for with-flagella bacteria to swim to the mammalian cells in the intestine and infect them. Why? Because the rich availability of so many nutrients enables motile bacteria to get enough energy to swim. But, without-flagella bacteria use this environment to conserve their energy, because they don’t need a lot of nutrients to survive.

b)    In an undernourished environment, without-flagella bacteria can still survive because they saved their energy from swimming under nutritional conditions. Bacteria with-flagella can convert to without-flagella under such conditions using their magic epigenetic switch! 

Researchers have designed vaccines using an epigenetic switch!

While still an under-explored domain, epigenetics has led to the development of intelligent vaccine designs. Such designs utilize these random switches to trigger mammalian immune response. The memory acquired after such an immune response acts as the basis for protecting the host body against pathogenic bacteria in the future. For instance, there are tiny molecules (also known as O-antigens) on the surface of Salmonella cells. When these molecules come in contact with mammalian immune cells, a protective immune response is triggered. An epigenetic switch determines the length of these antigens and, in turn, the antigens determine the intensity of mammalian immune response. The mammalian immune system recognizes shorter antigens faster than long ones, in turn triggering an early response against Salmonella.

In summary, epigenetics serves as a contributing factor for bacterial evolution in response to surrounding environmental conditions. Understanding the mechanisms of the epigenetic switches can help pave a path to control bacterial evolution for a specific task, like vaccine design. 

Link to the original post: Leise Riber, Lars Hestbjerg Hansen, (2021) Epigenetic Memories: The Hidden Drivers of Bacterial Persistence? Trends Microbiol 2021 Mar;29(3)

Other references

1.     Koirala, S., Mears, P., Sim, M., Golding, I., Chemla, Y. R., Aldridge, P. D., & Rao, C. V. (2014). A Nutrient-Tunable Bistable Switch Controls Motility in Salmonella enterica Serovar Typhimurium. MBio, 5(5), e01611-14.

2.     Michael Irving (2021). Experimental vaccine forces bacteria down an evolutionary dead end. New Atlas

Featured image: Author’s design