Revealing a regulatory divide
Mammalian genomes display large differences where the regulatory proteins of their embryonic stem cells bind
Published online 18 August 2010
Gene regulation in mice and humans has diverged substantially during the 75 million years since they shared a common ancestor, according to a recent study by Guillaume Bourque and co-workers at the A*STAR Genome Institute of Singapore1. Their findings suggest that more careful research is needed into such differences between the two species, particularly as mice are used as a primary model for humans in medical research.
In a direct comparison of the mouse and human genomes, the researchers found that two key proteins that regulate the activity of genes in embryonic stem cells bind only at about 5% of the same sites. This implies that the genes that are switched off and on, and the timing of the switching, are likely to be different between mice and humans. Up to 25% of the binding sites are found in repeat sequences frequently referred to as ‘junk’ DNA, meaning that more of the genome plays a role in gene regulation than previously thought.
Bourque and his co-workers used a technology called ChIP-Seq, in which specific DNA-binding proteins are fixed in place on the genome, which is then chopped into small segments. Pieces linked to these proteins are then retrieved by means of binding to an antibody, and the DNA to which they are linked is sequenced and identified.
The researchers focused on three regulatory proteins — the transcription factors OCT4 and NANOG that play a significant role in preventing embryonic stem cells from specializing, and CTCF, which is thought to preclude interactions between gene enhancers and promoters.
They found that while few binding sites for OCT4 and NANOG were conserved between the two species, up to half the binding sites for CTCF were the same. In the case of OCT4, the researchers demonstrated that the locations of the binding sites correlated with regulation of the activity of nearby genes.
Even though the elements of controlling pathways are the same, Bourque says, the details of regulation are different. As a substantial amount of medical research is undertaken using the mouse as model organism, information as to how their genes are regulated is of critical importance.
Such differences between genomes, however, are not limited to species. “Even between the genomes of individual humans, there are a lot of equivalent differences — and we are studying this now,” explains Bourque. “These regulatory differences may provide answers to questions such as why certain people are susceptible to a disease, or are responsive to a particular treatment.”
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore
- Kunsarso, G., Chia, N.-Y., Jeyakani, J., Hwang, C., Lu, X., Chan, Y.-S., Ng, H.-H. & Bourque, G. Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nature Genetics 42, 631–634 (2010). | article