Researchers at the University of California San Diego say they have identified a key factor that partially unravels nucleosomes and thus opens the way for genes to activate.
The identification of NDF, or nucleosome destabilizing factor, is described (“NDF, a Nucleosome Destabilizing Factor That Facilitates Transcription through Nucleosomes”) in Genes & Development. The scientists say the finding provides a new perspective on how genes are turned on and off—knowledge useful in the study of human diseases such as cancer, which can be caused by improper gene activity.
“Our understanding of transcription by RNA polymerase II (Pol II) is limited by our knowledge of the factors that mediate this critically important process. Here we describe the identification of NDF, a nucleosome-destabilizing factor that facilitates Pol II transcription in chromatin. NDF has a PWWP motif, interacts with nucleosomes near the dyad, destabilizes nucleosomes in an ATP-independent manner, and facilitates transcription by Pol II through nucleosomes in a purified and defined transcription system as well as in cell nuclei,” write the investigators.
“Upon transcriptional induction, NDF is recruited to the transcribed regions of thousands of genes and colocalizes with a subset of H3K36me3-enriched regions. Notably, the recruitment of NDF to gene bodies is accompanied by an increase in the transcript levels of many of the NDF-enriched genes. In addition, the global loss of NDF results in a decrease in the RNA levels of many genes. In humans, NDF is present at high levels in all tested tissue types, is essential in stem cells, and is frequently overexpressed in breast cancer. These findings indicate that NDF is a nucleosome-destabilizing factor that is recruited to gene bodies during transcriptional activation and facilitates Pol II transcription through nucleosomes.”
“It's a special privilege to discover a new activity in the regulation of our genes,” said James Kadonaga, Ph.D., Distinguished Professor of Molecular Biology and the Amylin Endowed Chair in Lifesciences Education and Research, adding that the breakthrough came as a result of postdoc Jia Fei's interest in factors that might disassemble or destabilize nucleosomes. “This novel approach led to the identification of NDF as a nucleosome destabilizing factor.”
When genes are turned on, RNA polymerase travels along the DNA and makes a working copy (RNA) of the DNA. Here, nucleosomes, which look like beads on the DNA chain, pose a problem because they block the passage of the polymerase. This led to the question: How is the polymerase able to travel through nucleosomes?
The answer emerged with the identification of NDF, which destabilizes nucleosomes and enables the progression of the polymerase. The researchers say NDF's makeup suggests that it is broadly used in perhaps all human cells and may play a role in disease.
“NDF is present at abnormally high levels in breast cancer cells, and the overproduction of NDF might be partly responsible for the uncontrolled growth of these cells,” continued Dr. Kadonaga. “Thus, the identification of NDF resolves an old mystery and reveals a new factor that may have an important role in many aspects of human biology.”