A trio of groundbreaking publications from researchers in Northwestern University's Physical Sciences-Oncology Center (PS-OC) report important methodological advances that will enable a better understanding of how gene expression is regulated, both in normal cells and in cancer cells. This knowledge could lead to the development of more effective therapeutic agents to treat cancer patients.
The three papers, published recently in the journals Nature Genetics, Nature Biotechnology and Nature, focus on nucleosomes, a basic unit of DNA packaging, and may help to uncover the rules governing gene transcription.
The late Jonathan Widom of Northwestern is senior author of the Nature paper that describes a new method for mapping nucleosomes. His longtime collaborator Eran Segal of the Weizmann Institute in Israel is senior author of two papers that build on his and Widom's earlier discovery of a "second DNA code."
"It is becoming increasingly clear that acquired mutations in the machinery that underlies the way in which DNA is packaged into chromatin are major drivers of the development of tumors in humans," said Jonathan Licht, M.D., the Northwestern PS-OC's senior investigator. Chromatin is a complex of DNA and proteins that when compacted forms chromosomes.
"The work of the PS-OC, including these new studies, has allowed the elucidation of the normal rules by which chromatin is arranged in the cell," he said. "This will help us to understand what's going wrong in cancer and how that might be remedied." Licht is the Johanna Dobe Professor and chief of the division of hematology/oncology at Northwestern's Feinberg School of Medicine and an associate director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Six years ago, Widom and Segal reported in Nature the discovery of a second DNA code that explains the placement of nucleosomes, spool-like structures in which the DNA loops around a protein complex. (The first code is DNA's genetic code, which specifies the composition of cellular proteins.) Nucleosomes control access to the DNA. Widom and Segal found there are certain DNA sequences that favor or disfavor the location of these nucleosomes.
Widom, whose research focused on chromatin packaging and gene regulation, and Segal, a computational biologist, continued their studies on sequence preferences for nucleosome formation as part of a project funded by Northwestern's Physical Sciences-Oncology Center.
Widom directed the center until his untimely death last year and was the William Deering Professor of Molecular Biosciences in the Weinberg College of Arts and Sciences. Segal has been a member of the center since its inception in 2009.
"This new work of Jon Widom's lab, reported in Nature, adds greatly to the ability to measure the locations of nucleosomes with unprecedented accuracy, which is needed to decipher the code in the DNA as reported in our two recent papers," Segal said.
In the papers by the Segal group, one in Nature Genetics and the other in Nature Biotechnology, Segal and his colleagues developed an elegant experimental system that allows them to accurately measure the effects of DNA sequences that disfavor the formation of nucleosomes on transcriptional regulation.
The new technology makes it possible to simultaneously introduce tens of thousands of DNA regions into tens of thousands of living cells -- each region in a separate cell -- in a planned and systematic manner, and to measure the results of each such change with great precision and within a single experiment.
Using this system, the Segal group demonstrated that sequences favoring the formation of nucleosomes do indeed have a significantly negative impact on transcription. Transcription is the copying of specific sequences in the DNA into similar molecules called RNA, which are intermediaries in the flow of information between the DNA and protein production. Both of the Segal papers acknowledge the intellectual contribution of Widom to their work.
The third paper, published in Nature and reporting on work completed in the Widom laboratory after his death, describes another major methodological advance. This novel technique permits the location of nucleosomes in the genome to be mapped with much higher accuracy than was previously possible. Not only will this technique enable a much better understanding of transcriptional regulation, but it should also help scientists to understand other features of DNA biology.
Ji-Ping Wang, who directs the bioinformatics core of the PS-OC, played a major role in the development of this technique.
"This is another example of how Jon's great knowledge in biochemistry and biophysics allowed him to suggest a way to scale up an existing experimental technique into modern tools that would allow genome-wide mapping of nucleosomes," Segal said. "Jon also was closely involved in our work and provided invaluable insights and suggestions into all aspects of the research."
The Northwestern Physical Sciences-Oncology Center focuses on applying physical sciences approaches to understanding the fundamental principles underlying aberrant gene expression in cancer. Funded by the National Cancer Institute, the center is a collaboration of the Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Megan Fellman | EurekAlert!
Researchers find new mutation in the leptin gene
24.06.2019 | Texas Biomedical Research Institute
Straight to the heart
24.06.2019 | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft
From June 25th to 27th 2019, the Fraunhofer Institute for Digital Media Technology IDMT in Ilmenau (Germany) will be presenting a new solution for acoustic quality inspection allowing contact-free, non-destructive testing of manufactured parts and components. The method which has reached Technology Readiness Level 6 already, is currently being successfully tested in practical use together with a number of industrial partners.
Reducing machine downtime, manufacturing defects, and excessive scrap
The quality of additively manufactured components depends not only on the manufacturing process, but also on the inline process control. The process control ensures a reliable coating process because it detects deviations from the target geometry immediately. At LASER World of PHOTONICS 2019, the Fraunhofer Institute for Laser Technology ILT will be demonstrating how well bi-directional sensor technology can already be used for Laser Material Deposition (LMD) in combination with commercial optics at booth A2.431.
Fraunhofer ILT has been developing optical sensor technology specifically for production measurement technology for around 10 years. In particular, its »bd-1«...
The well-known representation of chemical elements is just one example of how objects can be arranged and classified
The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...
Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.
Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...
Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.
The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...
29.04.2019 | Event News
17.04.2019 | Event News
15.04.2019 | Event News
24.06.2019 | Agricultural and Forestry Science
24.06.2019 | Life Sciences
24.06.2019 | Medical Engineering