We can write out the sequence of the genome, but the three-dimensional structure of the molecule is important to its function as well. Now researchers at St. Jude Children's Research Hospital have generated a three-dimensional map of the mouse genome for the first time. Their work has revealed new insights into how the genome is organized and what it does during development, which can help us learn more about human developmental disorders. The findings have been reported in Neuron.
"Understanding the way cells organize their genomes during development will help us to understand their ability to respond to stress, injury and disease," said Michael Dyer, Ph.D., chair of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute investigator.
In this work, the scientists concentrated on the genomes contained in the nuclei of rod cells in the mouse retina, which sense light. As the retina develops in the mouse, over 8000 genes are activated or deactivated, and thousands of expression regulators are involved. Using a technique called ultra-deep chromosome conformation capture or Hi-C analysis, the researchers were able to make a map of the interactions between regulators and genes in mouse rod cells.
The organization of the genome was found to be changing in surprising ways at various developmental stages. "These changes are not random, but part of the developmental program of cells," noted Dyer.
The researchers also identified interactions between regions of the genome that encourage expression - promotors and enhancers, at different retinal development stages. They used machine learning to track how the organization of the genome was altered over time, and how easy it is to access certain regions so that the genes they contain can be expressed.
In this study, the scientists also observed a super-enhancer, which has a powerful regulatory effect on genes. It was active in a specific cell type at one particular stage. Importantly, super-enhancer function has been found to go awry in developmental brain cancer.
The super-enhancer influenced a gene called Vsx2, and when it was removed, the researchers found that one type of neuron, called bipolar neurons, was totally eliminated, although no other effects were seen. However, if the Vsx2 gene itself is deleted, there are many impacts on retinal development. This super-enhancer effect, therefore, seems to be very specific to bipolar neurons.
Data from the study and an instructional video can be found at St. Jude Cloud.
From the video above, learn more about a 3D map of the human genome that was generated several years ago and reported in Cell.