Scientists Advance Understanding of DNA Responsible for Diseases
Collaboration Produces CAPTURE, a New System That Gives Researchers More Insight in the Human Genome
Dr. Michael Q. Zhang and Dr. Yong Chen (right) examine test results from their new system of isolating and analyzing the factors that regulate human DNA.
Researchers from the School of Natural Sciences and Mathematics at The University of Texas at Dallas have teamed with colleagues at the UT Southwestern Children’s Medical Center Research Institute to create a new method for understanding the causes of genetic diseases, such as sickle cell anemia and some cancers.
The new system allows researchers to define the molecular structures that control the activity of regulatory DNA sequences in the human genome.
Dr. Michael Q. Zhang and postdoctoral researcher Dr. Yong Chen from Zhang’s Computational Biology Laboratory — along with assistant professor of biological sciences Dr. Zhenyu Xuan — collaborated on the formulation of the system called CAPTURE, or CRISPR Affinity Purification in situ of Regulatory Elements. Their work was published in a recent issue of the journal Cell.
“CAPTURE allows us to isolate and analyze all the factors that regulate our DNA,” said Zhang, the Cecil H. and Ida Green Distinguished Chair of Systems Biology Science. “This could open the door to learning how different proteins control genome function in cancer and stem cells. It’s a potent tool to decipher the genetic abnormalities that cause a wide range of diseases.”
The genome, which is the complete complement of human DNA, includes protein-coding genes as well as noncoding regions that regulate where and when other genes are activated. Despite the genome’s vast size, only 2 percent of it encodes for proteins. The remaining noncoding regions have repeatedly been identified as potential drivers for disease by human genetics and cancer studies.
“CAPTURE allows us to isolate and analyze all the factors that regulate our DNA. This could open the door to learning how different proteins control genome function in cancer and stem cells. It’s a potent tool to decipher the genetic abnormalities that cause a wide range of diseases.”
A better understanding of these regulatory regions, and the underlying principles that guide them when genes are turned on and off, is necessary to uncover how diseases develop and to find new treatments. However, the tools to identify these noncoding regions and to understand how they work are limited. The new system provides an in-depth look at these regulatory genetic elements.
In addition to regulatory proteins, called transcription factors, gene function also is affected by how the DNA molecule is folded up to fit inside a cell’s nucleus. Proteins called histones help compact the DNA strand, and the combination of the two forms chromatin. The three-dimensional folding of the chromatin results in distant areas of the genome interacting with one another.
The CAPTURE method has its origins in CRISPR/Cas9, a molecular system for precisely editing the human genome. CAPTURE isolates specific DNA segments so that researchers can identify what those segments regulate and what proteins are associated with them.
“Our method serves as a magnifier for comprehensive and unbiased analysis of locus-specific regulatory compositions,” Zhang said. “It is the first time we can pull down the local enriched proteins as well as long-range chromatin interactions.”
Zhang and his colleagues applied CAPTURE to a genomic region that includes genes whose mutations cause inherited blood disorders such as sickle cell disease and beta thalassemia.
“Our method successfully detected not only the known transcription factors and chromatin interactions, but also numerous unstudied gene interactions for this region,” Zhang said. “Combining this method and our previous results of 3-D chromatin architecture dynamics in early development, we’re moving toward understanding the mechanistic insights of genome structure and function in development and disease.”
The study was supported by the Cancer Prevention and Research Institute of Texas, the National Institutes of Health, the American Cancer Society, the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, the Cecil H. and Ida Green Center for Systems Biology at UT Dallas, the Welch Foundation and the American Society of Hematology. Other contributors to the study were from Fudan University in China and the Chinese Academy of Sciences.
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