Without the jargon, please!

 
The classic epigenetic landscape by C.H. Waddington. Waddington developed his landscape to illustrate how a cell might progress along a series of different pathways from the same starting point, to produce different cell-types. 

The classic epigenetic landscape by C.H. Waddington. Waddington developed his landscape to illustrate how a cell might progress along a series of different pathways from the same starting point, to produce different cell-types. 

 

What on earth is an enhancer, and what does it do?

We tend to think of genes being turned on and off by events that happen at the start of the gene, where the DNA starts to be read. However, in practice the genome adopts a complex 3D organisation, which means that different parts of the same chromosome can 'loop' over long distances to touch each other. Where this occurs, these looped regions can also turn on and off gene expression. These regions are called enhancers; they are often located tens-of-thousands (or even millions!) of DNA bases away from the start of the gene that they control. Enhancers are critically important for driving cell-specific patterns of gene expression, and in many cases a single enhancer can control the expression of many different genes.

Unravelling life's mysteries.

Unravelling life's mysteries.

How do we turn genes on and off in cells?

In complex organisms, such as humans, all of the information needed to describe every cell-type is coded for in the DNA present in every cell. As an organism develops, in order to produce different cell types (e.g skin, liver, hair, heart-muscle), these genes must be turned on and off in different patterns. In practice, this is done by changing the way that DNA is packaged.

In cells, DNA is wrapped around protein structures called nucleosomes to form a structure known as chromatin. If a gene is tightly packed in chromatin, it tends to not be read and the information stored in that gene is not used by the cell. If the DNA is loosely packed, the gene can be read and its information used. This switch is regulated by chemical modifications - sometimes known as epigenetic modifications -  on the nucleosomes themselves. 

These modifications are produced by an army of protein enzymes, called epigenetic enzymes, that work across the entire genome to turn on and off different patterns of genes (when DNA in a gene is read, its is said to be expressed, a process known as gene-expression). This mechanism means that the genes expressed in one cell type can be entirely different from these expressed in another cell type, causing the cells to be different from each other.

Controlling gene expression. It's really simple...

Controlling gene expression. It's really simple...

So what about eRNAs?

Enhancers that are involved in controlling gene expression, are regions of chromatin where DNA is loosely packed, and where many of the proteins that turn genes off-and-on can bind. This organisation means that these proteins can also read the sequence of DNA at enhancers, just like they would at a regular gene. However, the sequence of DNA at enhancers doesn't code for proteins like DNA at genes does. The molecule that DNA is read into - RNA - is said to be non-coding when it is made at enhancers. These non-coding RNAs produced at enhancers are called enhancer-RNAs, or eRNAs. Because they don't code for proteins, they are often considered to be "Genomic-Junk" molecules. However, this turns out not to be the case, eRNAs can be important for controlling gene expression. 

What do we do, and why is it important?

Our work showed that one method used by eRNAs to control gene expression is to bind to epigenetic enzymes and regulate their activity. This means that, by changing how these enzyme-machines work, eRNAs can control the epigenetic modifications on chromatin and therefore they control whether genes are turned on and off. Understanding this process is important, because it is now widely recognised that many of the mutations that result in disease, or cancer, occur in clusters at enhancer regions. Because these regions don't code for the proteins that make up cells, it isn't at all clear how they can cause disease. One possibility that we are exploring, is that mutations in eRNAs cause disease by changing the regulation of epigenetic enzymes, so that in these cells, normal, healthy patterns of gene expression become disrupted.