St Jude’s researchers create a first-ever 3D genome for understanding genes
Researchers move beyond sequencing and create a 3D map of a mouse genome
Just like the pirates on a treasure hunt, now St. Jude Children’s Research Hospital researchers have created the first-ever 3D map of a mouse genome and used this to discover scientific gold! This scientific gold includes insight from machine learning into the genomic organization as well as the function during development. The research study on 3D genome for understanding genes appears today in the journal Neuron.
Michael Dyer, Ph.D., the chair of the St. Jude Department of Developmental Neurobiology and Howard Hughes Medical Institute investigator, said that understanding the way cells organize their genomes during development will help the researchers to understand their ability to respond to stress, injury, and disease. Dyer and Xiang Chen, Ph.D., assistant member of the St. Jude Department of Computational Biology, are the corresponding authors of the research study published.
The research study focused on light-sensing rod cells in the retina of the mouse. More than eight thousand genes are turned on or off during retinal development. And thousands of regulatory regions across the genome also play a crucial role in this. Scientists used a technology called ultra-deep chromosome conformation capture or the Hi-C analysis to map those interactions in mouse rod cells.
Formerly, 3D genomics has focused primarily on understanding the regulation of specific genes and worked with cells growing in the laboratory.
Using an integrated analysis of data from a variety of sources and even machine learning, investigators showed that the genomic organization changed in surprising ways at different stages of development. And these changes are not random, but a part of the developmental program of cells, Dyer added.
Dyer and his colleagues have now used the same approach to create a 3D genome of the mouse cerebellum. This is a brain structure where medulloblastoma can develop. And medulloblastoma is one of the most common malignant pediatric brain tumors.
As we know the human genome is encoded in the three billion chemical bases of human DNA. The first human genome was completely sequenced in the year 2003. Since then scientists have used the technology to identify and also to study inherited or acquired genomic alterations that can lead to cancer and other diseases.
Stretched its entire length, DNA from a single human cell measures about 6 feet long. To function, the DNA is packaged into a microscopic bundle that fits into the nucleus of cells. The resulting DNA loops can bring together otherwise distant regions of the genome. Key details, including a 3D map of loops and the interactions they fostered, were largely a mystery.
The current study captured long-distance interactions between promoters (DNA regions that promote gene expression) and enhancers (regions that increase gene expression) at different stages of retinal development. Researchers also tracked changes in genome organization during development. That included the first use of machine learning to gauge how easily accessible genes are for transcription. Chen led the machine-learning effort.
The study also included the first report of a powerful regulator of gene expression, a super-enhancer, which worked in a specific cell at a specific stage of development. The finding is important because super-enhancers can be hijacked in developmental cancers of the brain and other organs.
In this study on 3D genome for understanding genes, the scientists determined that when a core regulatory circuit super-enhancer for the Vsx2 gene was deleted, an entire class of neurons (bipolar neurons) was eliminated. No other defects were identified. Deletion of the Vsx2 gene causes many more defects in retinal development so the super-enhancer is highly specific to bipolar neurons.
Scientists developed a genetic mouse model of the defect that scientists are using to study neural circuits in the retina.