A completely new area of genetic research is on the rise. In the past two years, RNA epigenetics has increasingly intrigued researchers with the enormous amount of new information it potentially contains. Scholars specializing in this process believe the details of RNA epigenetics may cause a true paradigm shift in how we see genetics. The ULB-Laboratory of Cancer Epigenetics, led by Prof. François Fuks, recently published its study on RNA hydroxymethylation in the top-notch journal Science.
We all know that our genetic code is made up of 4-letter combinations: A, T, G and C for DNA, and A, U, G and C for RNA. However, much more information is hidden in the DNA and RNA than any mere sequence of 4 letters can reveal. Each of the molecules represented by these letters can be tweaked with specific chemical reactions, which can have a huge impact on the functionality of the DNA/RNA sequence. This process in which external factors influence our genetic makeup is called epigenetics.
Only scratching the surface
DNA modifications have been studied for quite a while, but less is known about analogous modifications to RNA. What we do know is that DNA can contain up to 10 possible nucleotide variants, compared to at least 150 alternative nucleotide forms in RNA. In recent years, RNA epigenetics has given us some groundbreaking revelations and has slowly started to change the way we see genetic regulation. Also, Belgian research is actively contributing to this rapidly unfolding field. The Laboratory of Cancer Epigenetics headed by Prof. François Fuks, also director of the newly created ULB-Cancer Research Center (U-CRC) has recently published its latest study in Science.
The concept of methylation as silencing mechanism and hydroxymethylation as activating mechanism is an oversimplification.
This fine piece of research concerns the occurrence and function of hydroxymethylcytosine (hmC), a modified form of cytosine, in RNA. The team of Prof. Fuks found that the coding sequences of mRNA are abundantly decorated with hmC residues. The presence of these modified cytosines could then lead to an increased translation of the RNA. It would seem as if hydroxymethylation is counteracting the silencing effects of methylation, but Fuks offers some additional insight:
“The concept of methylation as silencing mechanism and hydroxymethylation as activating mechanism is an oversimplification. We now know that both processes can have activating and repressing effects, mostly dependent on the regions where they are occurring. A lot of questions still remain unanswered. How are these processes interacting with each other? Does hydroxylation of methylcytosines always lead to demethylation, for instance? We simply do not know yet.”
Flies over mice
In an unusual choice of model organism for a cancer research group, the fruit fly Drosophila was used. Fuks explains: “We are used to working with mammalian cells for cancer research. However, DNA hydroxymethylation is an important confounding factor. In Drosophila, methylation and hydroxymethylation of DNA does not occur, so when we study hmC molecules in this organism, we can be confident that they are originating from RNA. Additionally, Drosophila contains only 1 Tet enzyme, dTet, which carries out the modification. Mammalian cells have 3 different Tet enzymes, slightly complicating the matter. With this in mind, we chose to use Drosophila because we wanted to study the fundamental biology and function of hmC.”
This function was further uncovered when the team decided to knock out dTet, completely inhibiting hydroxymethylation. Brain development in the Tet-deficient Drosophila embryos was seriously impaired, and none of the embryos developed into full grown flies. The lethality of this mutation shows that dTet and hmC are involved in basic cellular processes, such as embryonal development.
Writing, reading and erasing cancer
Epigenetics is clearly essential for correct biological function. In this respect, it comes as no surprise that epigenetic processes are often dysregulated in cancer. Fortunately, epigenetic drugs are already in development.
Any big pharmaceutical company now has a department on epigenetics, looking for inhibitors of epigenetic processes.
“For certain types of leukemia, the most often used drugs target the epigenetics. Cancer epigenetics is already a reality in the clinic, and there is a lot of interest in further expanding upon that theme. Changing epigenetics is a lot easier than changing entire genes, such as tried in gene therapy. These so-called epi-drugs are rapidly improving. First-generation epi-drugs targeted the ‘writers’ of epigenetic changes, the enzymes actively modifying nucleotide sequences. The second and third generations targeted the ‘eraser’ and ‘reader’ enzymes of epigenetic changes, expanding the possibilities of manipulating epigenetics. For RNA, this research is still in its infancy, but some really exciting discoveries are being made!”
Delatte, Benjamin, et al. "Transcriptome-wide distribution and function of RNA hydroxymethylcytosine." Science 351.6270 (2016): 282-285.
Image right: Brain malformation in dTet-deficient fruitflies