The humble mouse shares a surprisingly high degree of its DNA sequence with humans, so it is little wonder that we have turned to these small creatures to help uncover some of the mysteries encoded within our own genome. While the ground-breaking task of sequencing the entire human genome was completed more than 10 years ago, understanding how the jumble of approximately 3 billion As, Ts, Cs and Gs (the bases that encode our whole genetic makeup) contains the information required to make us human is an ongoing task and an undeniable challenge. One startling discovery was that the vast proportion of our genome is not gene-encoding and appears to have no function whatsoever, leading to it being referred to as 'junk' DNA. However some of these stretches of DNA have been highly conserved through evolution and it is becoming increasingly apparent that not all non-coding DNA is necessarily 'junk'.
Bing Ren and colleagues at the Ludwig Institute for Cancer Research and the University of California, San Diego have revealed how they have mapped some of these non-coding sequences in the mouse genome and assigned functions to them. Where and when certain genes are turned on or off is regulated by a variety of factors, including specific regions of non-coding DNA sequence that are located close to the gene. These sequences are called 'cis-regulatory elements' and proteins bind to these sequences to regulate gene expression. The team in San Diego used a method called ChIP-Seq, which is a high-throughput and sensitive method to sequence the DNA regions bound to certain target proteins, in 19 different tissues and cell types from the mouse. They used target proteins that are involved in promoting, enhancing or repressing gene expression to identify nearly 300,000 cis-regulatory elements, constituting 11% of the whole genome. Interestingly, they found that enhancers for particular genes were often organised in clusters with the promoters for those genes, and that these clusters were probably physically separated from other such clusters within the genome.
Various mouse tissues and cells were used in this study including brain, liver, heart and embryonic stem cells and this has meant that the findings have begun to shed some light on how genes are regulated in a tissue- and developmental- specific manner. For example, enhancers that were important in the growth and development of neurons were active in the embryonic mouse brain, whereas enhancers associated with genes for transmission of nerve impulses were more dominant in the adult brain.
The data from this study may help us to understand the non-coding sequences within our own genome given that the regulatory regions identified made up roughly 70% of the non-coding DNA sequences common between mouse and human. Furthermore, many human diseases, including cancer, are associated with misregulated gene expression and so techniques such as this can begin to illuminate how this occurs and even begin to identify potential therapeutic targets.
Shen et al. A map of the cis-regulatory sequences in the mouse genome. Nature. 2012 Jul 1. doi: 10.1038/nature11243