A Q&A with Dr. Kavitha Sarma
Dr. Kavitha Sarma runs an independent lab focused on nucleic acid structures called R-loops that contain both DNA and RNA and assist in gene expression. Dr. Sarma, associate professor in Wistar’s Gene Expression and Regulation Program, recently published a paper in Molecular Cell about genomic structures — specifically, G-quadruplexes and R-loops.
R-loops are bubble-like structures that can form in our DNA, and they can affect how genes are expressed — whether genes are turned on or off. G-quadruplexes form on the single-strand DNA of R-loops and can stabilize R-loops. In her research, Dr. Sarma found that R-loops and G-quadruplexes can influence the binding of a protein called CTCF, which helps fold and organize our DNA. This folding process is important for gene expression. If the genome is folded correctly, that allows genes to be expressed the way they should be. But if the genome is folded incorrectly, it can cause faulty patterns of gene expression, which can potentially lead to disease and cancer. R-loops and G-quadruplexes can play a role in cancer and disease by recruiting CTCF in a way that promotes faulty gene expression.
In your paper, you found that R-loops and G4s had an interesting relationship with a certain molecule. Could you explain that finding?
In every cell nucleus in your body, you have something like two meters of DNA, if you were to unravel it completely into one long double helix. Just to make genetic information physically fit in your body, the genome has to be compacted, and that needs to happen in every single cell, too.
There are many proteins that function in genome folding. We found that R-loops and G4s can influence the binding of one of these proteins - CTCF, which has a very important role in how the genome is folded.
This folding process, which also serves as a kind of information organization process, is important for how cells develop and specialize in our body. For example, the way a neuron’s genome is folded and expressed will be different from the genome folding and gene expression of a pancreatic cell because the two cell types fulfill different purposes. Epigenetic regulation from factors like genome folding allows for a diversity of gene expression — which, in turn, allows for a diversity of cell types and functions.
So, if a genome is folded correctly in the nucleus and the right regions are next to each other, that has a positive effect, and genes are expressed the way they should be. But if CTCF folds the genome incorrectly — for example, if R-loops and G4s form and facilitate CTCF binding to regions where it isn’t supposed to bind — we might see incorrect patterns of gene expression and the kinds of dysregulation you’d find in cancer and disease.
What are the pathogenic implications of CTCF recruitment?
This finding, that G4s affect CTCF, tells us that the genome misfolding in disease can be at least partially due to the formation of R-loop structures. In addition to developmental disorders, R-loop and G4 structures can play problematic roles in cancer because they’re what we call co-transcriptional. When transcription happens, these structures tend to accumulate — they tend to become stabilized. Hypertranscription that occurs in many cancers can contribute to genome misfolding through R-loop and G4 formation, which can further reinforce faulty gene expression patterns by essentially rewiring the genome.
What does this rewiring cycle tell us about the epigenetics of cancer and disease?
I think that this research gives us a good roadmap for looking for therapeutics down the line, because a better understanding of epigenetic regulation gives us deeper insight into how disease states work at a very localized level.
We know that R-loops and G4s can alter CTCF binding and change genome folding. Going forward, we can identify pathogenic contacts that occur because of these genomic structures and try to correct them. This is how foundational research — understanding processes that weren’t understood before — can lead to advances in the science of human health.