Debunking myths on genetics and DNA

Wednesday, November 2, 2011

A battle for transcription regulates bacterial conjugation

Genetic information is transmitted in two modes: when we talk about the slow accumulation of mutations across generations, we are talking about vertical gene transfer, in other words, the transmission of genetic alleles from the parents to the offsprings. Genetic material can also be transferred "horizontally" when an organism incorporates another individual's genetic material without being the individual's offspring. A genetic chimera is an example of a horizontal gene transfer.

You can picture horizontal gene transfer as a sudden increase in genetic diversity. While most of evolution studies have focused on vertical gene transfers, horizontal gene transfer has been shown in some milestones in the evolution of life: for example mitochondria have originated through a horizontal transfer event from an eukaryotic cell which incorporated a bacteria by symbiosis.

Bacterial conjugation is the horizontal gene transfer process through which bacteria exchange genetic material. That's what makes bacteria so efficient at developing antibiotic resistance. It takes many mutations to find the ones that confer resistance, but once the mutation appears in the population, it spreads to other individuals very quickly. How?

Besides the usual strand of chromosomal DNA, bacteria have a separate DNA molecule called plasmid, which is a short bit of double-stranded, circular DNA (circularity makes it more stable). The plasmid is what gets transferred during bacterial conjugation. The process involves a donor cell and a recipient cell. The donor has the plasmid with the gene that confers antibiotic resistance, and the recipient doesn't. Once the donor "recognizes" that the nearby cell lacks the resistance gene, a channel gets opened from the donor cell to the recipient. One of the two DNA strands in the plasmid is cut, unrolled, and transferred to the donor cell through the channel. Both cells then produce the complementary strand, and the original plasmid is restored in both.

But how does the donor cell know that the nearby cell does not have the resistance gene? Each cell communicates by expressing different peptides and "sensing" the neighbor's peptides through a mechanism called "Type 4 secretion system," or TFSS. Once it "detects" that the neighbor doesn't have the resistant gene, conjugation is activated.

Chatterjee et al. [1] studied the mechanism in Enterococcus faecalis and presented a mathematical model (supported by experimental data) of conjugative transfer regulated through convergent transcription from antagonistic genes, in other words, genes that sit on opposite strands of the DNA and hence compete for transcription.

Two genes on the plasmid regulate conjugation: gene Q activates it, and gene X represses it. Now, here's the interesting bit: X and Q are overlapping, sense-antisense genes. This means that they get transcribed in opposite directions. Remember: transcription is the process that converts DNA into a single strand of RNA, which is what the cell needs in order to produce proteins. Think of the single stranded RNA as a list of instructions that needs to get through. If the RNA from gene Q is produced, then conjugation is activated and the plasmid transfer occurs. If RNA from the X gene is produced instead, conjugation is repressed.

RNA transcription is carried out through an enzyme that "slides" through the DNA much like a zipper. The novel idea of this paper is that if the genes are transcribed in opposite directions, the two enzymes transcribing each gene will "collide" with a certain probability. One enzyme slides in one direction, the other in the opposite direction, and depending on how frequently the process takes place, the two enzymes "crash", interrupting the transcription process, as illustrated in the graphics below (by Kaitlyn Pladson and Ranja Sem).

Each time a collision happens, incomplete strands of complementary RNA are created. Complementary RNA strands will "stick" together and when that happens they can no longer be used to make proteins. As a result, the two enzymes are effectively competing against one another for which of the two genes gets transcribed: where and how frequently they collide regulates the activation of either the gene X or the gene Q, thus initiating or repressing bacterial conjugation. This kind of competition between the two enzymes due to the relative expressions of sense and antisense genes is what regulates the switch between activating the conjugation or repressing it. In the end, the enzyme that is able to zip through the gene faster ultimately "wins" because it is able to produce a larger concentration of RNA strands.

As I read the paper, I couldn't help but wonder how many other biological mechanisms are regulated by this sense-antisense antagonistic transcription. We know there are sense-antisense genes in the human genome, and little is known about their function. This study sheds new light into these DNA regions and advocates for more equivalent research in the human genome. As Chatterjee et al. conclude in their paper, "The fact that convergent transcription is ubiquitous and has persisted in evolution is perhaps an indication that such gene organizations confer fundamental mechanisms of gene regulation. With such a wide range of possible outcomes, using subtle structural tuning, convergent transcription may be highly adaptable to become a robust controller for many complex cellular events."

[1] Chatterjee A, Johnson CM, Shu CC, Kaznessis YN, Ramkrishna D, Dunny GM, & Hu WS (2011). Convergent transcription confers a bistable switch in Enterococcus faecalis conjugation. Proceedings of the National Academy of Sciences of the United States of America, 108 (23), 9721-6 PMID:

Photo: morning glories. Canon 40D, shutter speed 1/400, focal length 85mm, f-stop 5.6, ISO 100.
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  1. That's all kinds of interesting. So bacteria can propagate genes and viruses can transcribe genes. Then there's the old run of the mill vertical inheritance. Are there more mechanisms?

  2. And what about the "jumping genes" that keep skipping around throughout our life? Is there more? Who knows! I keep learning more and more, and the architecture of the genome keeps baffling me with all these complex mechanisms that are intricately laced together. My next posts will focus on RNA editing, which turns out is not just a "middleman" but has many more regulatory functions than originally thought.

    One thing is for sure: we are past the time when we thought that genes were the bread and butter of genetics, and it all came down to them (traits, diseases, etc.) Life is way more complex than that!


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