New Discoveries from NU Physical Sciences-Oncology Center Uncover the “Rules” Governing Gene Transcription

A trio of ground-breaking publications from researchers in Northwestern’s Physical Sciences-Oncology Center (NU-PSOC) has revealed important new methodological advances that have led to a new understanding of the forces governing the regulation of gene expression.   This field is the bedrock for understanding the fundamental aspects of health and disease as it is the “decryption” of the messages carried in our genes that is the important first step in determining which proteins, the major “working” molecules in our cells, are produced in response to changes in the cellular environment.  Regulation of the expression of genes is very tightly controlled in normal cells and aberrant expression is associated with a broad range of diseases, especially cancer.  The length and complexity of DNA requires that it be tightly bundled in cells and the question of how specific genes are accesses by the cell’s decrypting molecules has been a question that has long tantalized researchers.

These new studies produced by the laboratories of Dr. Eran Segal, a collaborator from the Weizmann Institute in Israel, and Drs. Jonathan Widom and Ji-Ping Wang have succeeded in pulling back the curtain on these most fundamental aspects of biology by developing highly sensitive methods to examine how genes are packed in the cell and the factors in terms of location, orientation, and organization of specific genes that affect the conditions under which genes are expressed.   Prof. Segal and colleagues, publishing in a June edition of Nature Biotechnology (volume 30: no. 6, pp. 521-530) has developed a method for high-throughput measurements of carefully designed large-scale promoter (DNA sequences that precede protein-coding regions of genes) libraries that will allow researchers to uncover the ‘regulatory code’ that translates DNA sequence into expression.  His lab has also demonstrated a mechanism for fine-tuning gene expression by changing DNA promoter sequences to disfavor the binding of proteins, known as histones which wrap DNA into inaccessible balls, can increase gene expression (Raveh-Sadka et al. Nature Genetics vol. 44 no. 7:  pp. 743-750, 2012).

This work is complemented by the recent publication in Nature(vol. 486 pp. 497-501, 2012) by Kristin Brogaard, a recent NU PhD working in collaboration with the NU-PSOC Bioinformatics Core, describing a new, highly sensitive method for examining the rules governing how DNA is wound up around histone proteins for compaction into cells.  The profound influence of Prof. Jonathan Widom, founding director of Northwestern’s Physical Science-Oncology Center, on this work is not diminished by his untimely death last July.   He guided the intellectual foundation and methodological approaches that led to these breakthroughs.

Jonathan Licht MD, Johanna Dobe Professor and Chief of the Division of Hematology/ Oncology in the Robert H. Lurie Comprehensive Cancer Center in the Northwestern University Feinberg School of Medicine and the NU-PSOC’s Senior Investigator commented “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.  The work of the PSOC has allowed the elucidation of the normal rules by which chromatin is arranged in the cell.  This will allow us to understand what’s going wrong in cancer and how that might be remedied.”

The Northwestern Physical Sciences-Oncology Center, a collaboration between the Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center, is funded by the National Cancer Institute with the goal of applying physical sciences approaches to understanding the fundamental principles underlying aberrant gene expression in cancer.