OCT 02, 2016 11:49 AM PDT

Decoy DNA Binding Sites Subtly Impact Gene Expression

WRITTEN BY: Carmen Leitch
Decoy sequences of DNA are able to interfere with gene expression, and in ways that are not yet well understood. New findings by researchers at Rice University, who used computer simulations to help them understand how complex molecular pathways are regulated in cells, have implications for the design of drug treatments.
 
NFkB molecule and DNA from Wikimedia Commons
 
The work was published in the journal Interface by lead authors Zhipeng Wang and Davit Potoyan who worked with biophysicist Poeter Wolynes. The takeaway message of the research, said Wolynes, is that instead of focusing only on certain molecular targets, manufacturers must investigate how drug products impact complete biological networks.
 
Transcription factors bind to DNA and exert an influence on gene expression. In this study, the researchers were focused on a network of cellular pathways that is affected by a family of transcription factors called NFkB. Dysfunction in the regulation of NFkB has been implicated in many diseases including cancer, arthritis, heart disease, and asthma.

NFkB works in conjunction with the enzyme complex IkB; gene expression is modulated to control events like cellular death, growth and differentiation, and the immune response to inflammation. Normally, NFkB binds to DNA, which prompts IkBa expression. However, some NFkB molecules bind to decoy DNA sequences instead of to functional targets. A recently discovered process called stripping then occurs in which all of the bound NFkB are released at once from the DNA, which stops transcription. This cycle of NFkB binding and unbinding is critical to the expression of many different proteins, but the importance of the seemingly non-functional decoy sites is not understood.
The recently discovered process of molecular stripping (top) shows how nature has evolved to cope with regulating master transcription factors like NFkB that engage in pervasive genome-wide binding. Rice University researchers have proposed a revised model, bottom, of the NFkB regulatory network that suggests novel strategies for more effective decoy therapy. / Credit: Wolynes Research Lab/Rice University
 
“Some transcription factors can bind to many sites, and sometimes this binding is nonspecific, with no apparent purpose. Traditionally, people look for things that change dramatically,” explained Potoyan, who is a postdoctoral researcher in Wolynes’ lab. “They look for something that turns on, something synthesizing, something degrading. Decoy binding doesn’t appear to be very interesting, but we’re saying it can influence system-level dynamics in a quiet way by sequestering transcription factors from being active in the nucleus.
 
“In this case, we illustrate the decoy problem with the NFkB example showing how decoys can change the frequency and modulate the amplitude of the circuit.”
 
Wolynes explained that IkB strips proteins both from all of the DNA binding sites without discretion. “One consequence is that it becomes harder to recognize an active site from a decoy, throwing a considerable monkey wrench into the bioinformatics problem of how to find interesting parts of the genome.”
 
Synthetic sequences of DNA have been used as drugs to try to control gene expression to a patient’s advantage, including attempts to treat NFkB misregulation. “But I don’t think these treatments are yet as successful as they could be,” Wolynes said. “This paper shows the effect of the decoys will be diminished by stripping. One of the ‘translational’ suggestions in this paper is you’ve also got to control the level of IkB to use decoys more effectively, and that suggests some kind of combination therapy.”
 
Wang, a graduate student at Rice, would like to see the team’s increasingly comprehensive models of gene networks used to aid drug designers. “I want to use physical chemistry and physics principles to provide quantitative guidance to translational researchers and physicians so they can better understand how to cure disease,” he said.
 
Source: Rice University, Interface
 
About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
JUN 11, 2018
Immunology
JUN 11, 2018
Post-Trauma Treatment Relieves System-Wide Immune Reaction
The immune response after a traumatic physical injury is essentially the same as a body-wide bacterial infection: inflammatory, systemic, and lethal. From...
JUN 13, 2018
Technology
JUN 13, 2018
Hemp Fabric Kills Staph Bacteria
Cloth made from hemp outperforms many other textiles in staph resistance....
JUL 12, 2018
Neuroscience
JUL 12, 2018
Understanding Vascular Dementia
Dementia is a growing problem for healthcare providers, patients, and families. It’s estimated that 47 million people are living with dementia worldw...
AUG 05, 2018
Genetics & Genomics
AUG 05, 2018
Newly ID'ed Lung Cell Changes Our Understanding of Disease
This rare type of cell seems to play a major role in cystic fibrosis....
AUG 13, 2018
Microbiology
AUG 13, 2018
Insight Into the Origins of Junk DNA - From Koalas
The human genome isn't only genes. There's also long, repetitive sequences with an unknown function and origin....
AUG 14, 2018
Microbiology
AUG 14, 2018
How Ebola Gets Into Cells
Researchers have learned how Ebola gains entry to cells, which can help us stop it....
Loading Comments...