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.