Musselman Lab's model of histone-DNA interaction could unlock targeted therapeutics
Did you know that every cell in our body has the same DNA inside but only uses the genes it needs to become the cell type that is? As an example, skin cells only use the genes needed to create all the proteins and components essential to becoming a skin cell. They leave all the other genes unused. The same is true for cells in our hearts, lungs, eyes, etc.
Catherine "Cat" Musselman, PhD, is a research scientist in the Department of Biochemistry and Molecular Genetics who studies how genes can be turned "on" or "off" within a field of science known as epigenetics. The term means "on top of" or "above" the genome. Musselman and her team study the chemical signals that are placed on top of genes. These signals control how the genes are used without changing the sequence of the DNA.
Epigenetics - or signals on top of the genome - are like the messages written in frosting on top of a cake. Some cakes have the message "happy birthday" on top, while others display "congratulations" or "happy anniversary." The messages act as a signal for the event the cake was made for but won't change the cake inside.
How are our genes stored?
Humans have about 20,000 genes that serve as instructions to make all the proteins needed for our bodies to be built and work. These genes are written in the chemical language of DNA, and incredibly, all of our genes are written on DNA strands that measure 6 feet inside each cell.
To keep the DNA organized inside each cell, these strands are carefully wound around a group of proteins called histones. Histones look like the plastic center of a yo-yo, and the DNA is the string that wraps around the center groove. This keeps the strand from becoming a tangled mess inside the cell.
Histones and DNA are attracted to one another due to their opposite chemical charges. Histones have an overall positive charge, and DNA has an overall negative charge. Histones function to package a huge amount of DNA into a very small space, and they also serve as signaling platforms (think of the "on" and "off" settings) to regulate access and use the underlying genetic material.
How do our cells know which genes to turn on and off?
Modifications to histones through the addition of a variety of small chemical groups are called post-translational modifications (PTMs). They play a role in turning genes "on" or "off." Histone PTMs are known to play a huge role in defining cell identity and allowing each cell to respond to the environment. This environment includes your diet, emotional stress, environmental toxins and infection. Histone PTMs change in response to all of these factors and can also be messed up due to genetic mutation, including mutation of the histones themselves.
Since histone PTMs are relatively easy to manipulate through changes to diet and drugs, they have high therapeutic potential. However, to understand how to best use histone PTMs to develop therapeutics that would allow us to change the way DNA is used, we must first understand how they are functioning.
Cracking the histone code
The Musselman Lab created a model of how the histones are interacting with DNA and how histone PTMs may alter or change these interactions. Their next steps are to test this model more thoroughly by investigating how targeted changes in histone PTMs and/or histone mutations change gene expression.
Some of these experiments have been done in partnership with a company called EpiCypher focused on discovering and studying key parts of the histone code. The Musselman Lab is focused on cracking the histone code and learning more about how we can use that knowledge to develop drugs that treat human disease.
