Jelena Ersj, assistant professor in the Department of Molecular and Cellular Biology and the Institute for Systems Genomics, is working on a $2 million R35 MIRA (Early Phase Investigator Research Award) from the National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS) to study the role of folding The paternal genome during evolution. Erceg also holds a joint appointment with the UConn Health Department of Genetics and Genomics.
Each copy of our DNA, stretched from end to end, is approximately six feet long. But it needs to fit into the nucleus of each cell about 10 microns wide – about 250 times smaller than a single raindrop. This problem is solved through a process known as genome folding.
Genome folding is the complex way our cells fold our long strands of DNA to fit them into that tiny nucleus. The key is that our cells still need to be able to access our DNA during development and throughout our lives.
If something goes wrong with this complex folding process, it could affect the interactions between genes and the regulatory elements that determine how much and when genes are expressed. This can cause problems such as deformed limbs or cancers.
Scientists are working to understand this complex problem from several angles. Erceg’s lab focuses on the role of maternal versus paternal transcription of our genes.
“There are examples that changing the fold can affect the function of essential genes, but there are also counterexamples that if you change the fold, you may not change gene expression,” Ersge says. “Therefore, there is some kind of controversy also in the area that we want to enrich by adding a layer of research into the genomes of the parents.”
Every cell in the human body contains two pairs of DNA – one from the mother and one from the father. This is why we may inherit our mother’s eye color but dad’s hair color. But these differences can also have implications for disease and development. Even a small change in DNA from a parent can alter how our DNA folds, leading to disease.
The main goal of Erceg’s study is to understand how the parental genome folds and is organized during development, from primary zygote to differentiation into every cell type in the body.
Erceg will also consider the tissue environment of the cells to determine how this affects genome folding.
“It’s important to look at cells in tissues and not just as isolated single cells without looking at the context in which they function normally,” Ersge says.
The ultimate goal of the Erceg study will be to assess the effect of heterozygosity on genome folding and disease susceptibility.
Almost half of the human genome is full of repeats. Erceg is interested in knowing where and how these repeats differ between the maternal and paternal genomes and what that means for health.
To study these goals, Erceg’s lab will use fruit flies. Fruit Files are a proven model for studying genetics because you can have a new generation of flies in just a few days. In addition, they have only four sets of chromosomes and scientists already know their genome sequence, which makes it easy to manipulate their DNA and monitor changes.
Erceg will use a technique known as Hi-C that will allow it to use single base pair differences to distinguish chromosomes from one another to determine which is maternal versus paternal. Then Erceg can directly observe how the chromosomes interact with each other in the nucleus.
“We’re going to use this genome tool to get a complete picture of the genome,” Ersig says. “And this is very powerful, because you can see many interactions at the same time and combine them with information on genome activity.”
You’ll also use microscopy to coat the chromosomes from the mother and father in different ways. This will allow her to visualize how these chromosomes interact and function in different types of cells as well as measure the exact fold dimensions.
“What the microscopy brings is that you start to see the images that you start to look at the actual 3D folding,” Ersge says.
A better understanding of the relationship between genome folding and how we inherit DNA from each parent could provide a stronger basis for personalized genomic medicine for chromosome-based diseases.
“Everyone is different, so those changes in which one sibling might be carrying another sibling carry something a little different,” Ersge says. “Entering into the field of personalized genomics medicine could help treat human chromosomal diseases.”