Articles / brain cancer

DNA loops matter for NFIA gene expression in brain tumors

The nuclear factor I-A (NFIA) gene is important for both normal brain development and brain tumor growth. One way to discover paths that can lead to brain malignancy is to first better understand the process of normal brain development. The Deneen lab has followed this strategy. They have studied the mechanisms by which normal brain cells regulate NFIA expression to gain insights into the process that leads to malignancy. They hope this approach might one day help design improved therapies to treat brain tumors.

Dr. Benjamin Deneen

“We began this project by studying how three components that regulate the expression of the NFIA gene interact with each other in the developing spinal cord in animal models,” said 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 glial cells, which represent about 70 percent of the cells in the central nervous system and support the functions of the neurons.

Gene expression, the process by which genes 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. They 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.

DNA forms thousands of loops, like those of a shoe lace. Many of these loops bring distant genes and specific gene control switches close together. This image presents examples of DNA loops formed during the regulation of gene CTCF. DNA loops also form during the regulation of NFIA in glioma cells. Credit: National Human Genome Research Institute/Darryl Leja.

“Our chick spinal cord system is a powerful model for screening and proving enhancer function,” said Deneen.

“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 factors 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 glioma, one of the most deadly forms of cancer. It has a 5 year progression-free survival rate of less than 5 percent,”  said Deneen, who also is a member of Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.

Dr. Stacey Glasgow

“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,” Glasgow said.

The DNA loops they had observed in normal glial cells also were present in glioma cells and 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.”

Find the complete study in the journal Nature Neuroscience.

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Other contributors to this work were Jeffrey C Carlson, Wenyi Zhu, Lesley S Chaboub, Peng Kang, Hyun Kyoung Lee, Yoanne M Clovis, Brittney Lozzi, Robert J McEvilly, Michael G Rosenfeld, Chad J Creighton, Soo-Kyung Lee and Carrie Mohila. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children’s Hospital, Dan L Duncan Comprehensive Cancer Center, Papé Family Pediatric Research Institute Portland, Oregon Health & Science University and the University of California San Diego.

This work was supported by grants from the National Institutes of Health (NS071153, K01CA190235 and 5-T32HL092332-08), Cancer Prevention Research Institute of Texas (RP150334 and RP160192), and Sontag Foundation.

 

Ana María Rodríguez, Ph.D.

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