Alexander Johnson of the University of California, San Francisco (UCSF), and colleagues, write about their discovery in the 22 April online issue of the Proceedings of the National Academy of Sciences.
When scientists first started unravelling DNA, there was an assumption that we would soon discover everything about how genes behave. At first, it was thought that the map of DNA for making an organism, the "genome", contained all the instructions for making the proteins that make the organism. And much of this was contained in a very small part of the genome, and the rest mysterious as it was, was treated as "junk" DNA.
Then we discovered there is another layer of heritable genetic information that is not held in the genome, but in the "epigenome", which contains instructions on how to interpret the DNA code of the genome to make proteins. And, surprise, surprise, some of the code for making the proteins of the epigenome was discovered to be "hiding" in the "junk" DNA.
And so we came to understand, for example, that the 23,000 or so genes in the human genome that are found in all the cells of our bodies, are expressed differently in different tissues and organs depending on gene regulation instructions held in the epigenome. The instructions are held in the form of different sets and combinations of transcription factors.
Now we also know that changes in these transcriptional components can lead to disease, and that a major source of diversity on our planet is due to the gradual rewiring of transcriptional circuits over evolutionary timescales.
A useful way to study transcription factors is to observe one-celled organisms like Candida albicans. This species of fungus typically resides without causing disease in the gut of humans and other warm-blooded animals. But it can also at times, manifest as the most prevalent human pathogen, causing a variety of skin and soft tissue infections in healthy people, and more serious disease in people with weak immune systems.
The contribution that knowledge of gut flora could make to our understanding of human disease was put into perspective recently in a study that showed the extent to which gut flora genes dwarf the human genome.
By studying specific features of C. albicans scientists can observe how changes in transcription circuitry lead to differences in appearance and behavior in the same species.
One lab that has been studying C. albicans for a while is that of Alexander Johnson and his team at UCSF. They study how the fungus interacts with host cells, other microbes in the gut, and how its transcription circuits have adapted it for the host.
One feature they are particularly interested in is a process called "white-opaque switching", which appears to be an important mechanism for C. albicans' ability to survive in the mammalian host. This switching, which is controlled by the epigenome, produces two distinct types of cell from the same genome. Each cell type is preserved for many generations, until about every 10,000 generations when random switching occurs. The types also look different, express different genes, and prefer different types of host tissue.
Apart from studying the individual features of the two types of cell that arise, Johnson and colleagues have also been investigating the switching mechanism itself.
Lke others, they already knew that five transcription factors regulate white-opaque switching. But when they dug deeper, they came across one they called Wor3 (white-opaque regulator-3), which seemed quite different, and that is the subject of their latest study.
They found Wor3 by looking for genes that were expressed only in opaque cells but contained a DNA sequence that one of the five known transcription factors could stick to (transcription factors, which are essentially proteins, do their work by binding to a specific part of the genome, a particular sequence of DNA).
In their study they explain how they found putting Wor3 into white cells made them turn opaque, and when they deleted it, opaque cells stayed opaque, even at temperatures that would normally turn them white.
"We demonstrate that ectopic overexpression of Wor3 results in mass conversion of white cells to opaque cells and that deletion of WOR3 affects the stability of opaque cells at physiological temperatures," they write.
But perhaps the most remarkable thing they discovered is that Wor3 most likely evolved quite recently compared to most other transcription factors.
"Bioinformatic analyses indicate that the Wor3 family arose more recently in evolutionary time than most previously described DNA-binding domains; it is restricted to a small number of fungi that include the major fungal pathogens of humans," they write.
Perhaps there are more families of recently evolved transcription factors still to be discovered, adding weight to the idea that more of the genome is actually coding for the epigenome than we previously thought:
"These observations show that new families of sequence-specific DNA-binding proteins may be restricted to small clades and suggest that current annotations -- which rely on deep conservation -- underestimate the fraction of genes coding for transcriptional regulators."
An important message to take from this study is it would seem there are still new things to discover, and surprise us, about genes and their regulation, and we should never assume we know it all, no matter how vast that knowledge becomes.
Written by Catharine Paddock PhD