Surprising ’Remodeling’ Property of Gene Regulation Process
Much like moving furniture around to create more space, cells dramatically rearrange their entire genome in order to allow the right genes to be turned on at the right time, new research at the University of North Carolina at Chapel Hill shows.
This extensive chromosomal "remodeling" is accomplished by moving DNA packaging structures called nucleosomes to different spots in the genome. Once a nucleosome is moved from a site, the appropriate gene then can be expressed much more efficiently.
The new findings appear online in the journal Nature Genetics. The study will be published in the August print edition.
The UNC researchers also discovered that when a gene needs to be turned off, the cell recruits the nucleosomes back to a particular location in the genome, thus helping to ensure that expression of the gene is stopped.
Nucleosomes are complexes of proteins that were thought to simply bind to genomic DNA and condense it into structures called chromatin that can fit inside a cell’s nucleus. It was historically assumed that nucleosomes were uniformly distributed throughout the genome and that this distribution was unchanging. The new study overturns this assumption, the UNC researchers said. "Except for at a few genes, it was traditionally thought that there was a monotonic organization of chromatin that did not vary throughout the genome," said senior author Dr. Jason Lieb, assistant professor of biology in UNC’s College of Arts and Sciences and a member of the Carolina Center for Genome Sciences. "But chromatin is a dynamic thing - much more dynamic than was once thought."
The study also suggested a new role for the nucleosome as a regulator of gene expression.
"We now know that nucleosomes mark territory," said co-author Dr. Brian Strahl, assistant professor of biochemistry and biophysics in UNC’s School of Medicine. "This chromosomal remodeling allows the work of gene expression to occur."
The study used the yeast genome as an experimental model to determine if chromosomal remodeling actually occurred. "The yeast genome is very simple compared to the human genome, but yeast are quite responsive to their environment," Lieb said.
By varying the food source given to the yeast, the authors demonstrated that the yeast genes required to process new nutrients lost their nucleosomes and were expressed.
They also showed that nucleosomes return to genes that need to be turned off when yeast are subjected to less than optimal growing conditions. This chromosomal remodeling discovered in yeast likely is directly translatable to the more complicated mammalian genome, the researchers said. "The entire machinery required to package DNA and express genes in yeast is very similar to that in humans," Lieb said. "Its application is likely the same in mammalian cells."
The study potentially paves the way for scientists to understand how chromosomal remodeling influences gene expression and regulation in human diseases such as cancer, Strahl said. "This is such a fundamental observation about the genome, but nobody had ever made it before," he added.
Support for the research came from the National Human Genome Research Institute and the National Institute of General Medical Sciences, components of the National Institutes of Health.
Co-authors with Lieb and Strahl are postdoctoral researchers Drs. Cheol-Koo Lee, department of biology; Yoichiro Shibata, biochemistry and biophysics; and Bhargavi Rao, Curriculum in Genetics and Microbiology.