Nav: Home

DNA looping architecture may lead to opportunities to treat brain tumors

September 11, 2017

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 spinal cord 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 glial cells, which represent 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. 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 glioma, 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."

-end-

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.

Baylor College of Medicine

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Best Science Podcasts 2017

We have hand picked the best science podcasts for 2017. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: Radiolab

Radiolab Presents: Anna in Somalia
This week, we are presenting a story from NPR foreign correspondent Gregory Warner and his new globe-trotting podcast Rough Translation. Mohammed was having the best six months of his life - working a job he loved, making mixtapes for his sweetheart - when the communist Somali regime perp-walked him out of his own home, and sentenced him to a lifetime of solitary confinement.  With only concrete walls and cockroaches to keep him company, Mohammed felt miserable, alone, despondent.  But then one day, eight months into his sentence, he heard a whisper, a whisper that would open up a portal to - of all places and times - 19th century Russia, and that would teach him how to live and love again. 
Now Playing: TED Radio Hour

Future Consequences
From data collection to gene editing to AI, what we once considered science fiction is now becoming reality. This hour, TED speakers explore the future consequences of our present actions. Guests include designer Anab Jain, futurist Juan Enriquez, biologist Paul Knoepfler, and neuroscientist and philosopher Sam Harris.