DNA looping architecture may lead to opportunities to treat brain tumors

September 11, 2017
A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI

The discovery of a mechanism by which normal brain cells regulate the expression of the NFIA gene, which is important for both normal brain development and brain tumor growth, might one day help improve therapies to treat brain tumors. The study appears in the journal Nature Neuroscience.

"We began this project by studying how three components that regulate the expression of the NFIA gene interact with each other in the developing in animal models," said corresponding author Dr. Benjamin Deneen, associate professor of neuroscience at the Center for Stem Cell and Regenerative Medicine and member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine.

The researchers studied mostly , which represent 70 percent of the in the central nervous system and support the functions of the neurons.

Gene expression, the process by which produce proteins, is regulated at different levels, in a coordinated fashion, but scientists don't completely understand how these levels interact. Deneen and his colleagues explored how three levels of gene regulation coordinated their activities to regulate NFIA gene expression. The researchers studied enhancers, (sections of DNA that are located at a distance from the NFIA gene and can influence gene expression), transcription factors (proteins that bind to enhancers) and the three-dimensional architecture of the associated DNA.

First, they identified enhancers involved in the regulation of expression of NFIA gene using a non-traditional approach. Instead of using bioinformatics to infer which sections of DNA probably have enhancer activity, they used living chick embryos to identify enhancer elements in the spinal cord associated with the expression of the NFIA gene.

"Our chick spinal cord system is a powerful model for screening and proving enhancer function," said Deneen, who also is a member of Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. "The system allowed us to identify multiple enhancers that operate in specific locations in the DNA and at different times, enabling us to pinpoint the transcription factors that regulate them. We also were able to determine how the DNA strands formed distinct 3-D architectures - DNA loops - that brought enhancers and transcription factor together closer to the NFIA gene, which led to the production of the NFIA protein."

Applying the new findings to glioma, a type of brain tumor derived from glial cells

"We extended these studies to , one of the most deadly forms of cancer. It has a 5 year progression-free survival rate of less than 5 percent," Deneen said.

"We had previously shown that NFIA is important for glioma formation," said first author Dr. Stacey Glasgow, a postdoctoral fellow in the Deneen lab. "In this study we wanted to know whether the 3-D DNA loops we saw in normal glial cells also formed in glioma and what would happen if we disrupted them."

The researchers found that the DNA loops they had observed in normal glial cells also were present in glioma cells. When they disrupted the DNA loops in normal glial cells, the cells did not express the NFIA gene and did not fulfill their expected development. When the researchers disrupted the DNA loops in glioma cells, the cells decreased the expression of NFIA and reduced proliferation.

"Altogether, our results open the possibility for a new approach to treat glioma in the future," Deneen said. "Disrupting the DNA loops required for NFIA expression could be a potential strategy to indirectly reduce NFIA expression and, as a result, reduce tumor proliferation."

Explore further: Research reveals development of the glial cell

More information: Stacey M Glasgow et al, Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis, Nature Neuroscience (2017). DOI: 10.1038/nn.4638

Related Stories

Research reveals development of the glial cell

April 11, 2012
A vast majority of cells in the brain are glial, yet our understanding of how they are generated, a process called gliogenesis, has remained enigmatic. Researchers at Baylor College of Medicine have identified a novel transcripitonal ...

Scientists Discover Mechanism Behind 'Paused' Genes

September 7, 2017
Northwestern Medicine scientists have discovered the mechanism driving a protein that influences transcription, a crucial step in gene expression. The study, recently published in Science, could lead to drugs that control ...

First roadmap of stomach cancer super-enhancers paves the way for new treatments

July 26, 2017
A*STAR researchers have homed in on a potential new way to diagnose and treat stomach cancer, through the mapping of an unprecedented catalog of almost 3,800 super-enhancers from stomach cancer tumor cells.

Molecular 'on switch' could point to treatments for pediatric brain tumor

February 24, 2017
Massachusetts General Hospital (MGH) researchers have identified a mechanism that controls the expression of genes regulating the growth of the most aggressive form of medulloblastoma, the most common pediatric brain tumor. ...

'Mysterious' non-protein-coding RNAs play important roles in gene expression

January 12, 2017
In cells, DNA is transcribed into RNAs that provide the molecular recipe for cells to make proteins. Most of the genome is transcribed into RNA, but only a small proportion of RNAs are actually from the protein-coding regions ...

Recommended for you

Now you like it, now you don't: Brain stimulation can change how much we enjoy and value music

November 20, 2017
Enjoyment of music is considered a subjective experience; what one person finds gratifying, another may find irritating. Music theorists have long emphasized that although musical taste is relative, our enjoyment of music, ...

MRI uncovers brain abnormalities in people with depression and anxiety

November 20, 2017
Researchers using MRI have discovered a common pattern of structural abnormalities in the brains of people with depression and social anxiety, according to a study presented being next week at the annual meeting of the Radiological ...

Deletion of a stem cell factor promotes TBI recovery in mice

November 20, 2017
UT Southwestern molecular biologists today report the unexpected finding that selectively deleting a stem cell transcription factor in adult mice promotes recovery after traumatic brain injury (TBI).

Brain cell advance brings hope for Creutzfeldt-Jakob disease

November 20, 2017
Scientists have developed a new system to study Creutzfeldt-Jakob disease in the laboratory, paving the way for research to find treatments for the fatal brain disorder.

Neuroscience research provides evidence the brain is strobing, not constant

November 17, 2017
It's not just our eyes that play tricks on us, but our ears. That's the finding of a landmark Australian-Italian collaboration that provides new evidence that oscillations, or 'strobes', are a general feature of human perception.

Brain activity buffers against worsening anxiety

November 17, 2017
Boosting activity in brain areas related to thinking and problem-solving may also buffer against worsening anxiety, suggests a new study by Duke University researchers.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.