DNA packaging may point to epigenetic biomarkers of disease

July 5, 2013 | by

Cells must efficiently pack enormous amounts of DNA into their tiny nuclei. How they do this, and the role this packaging plays in disease development, remains a mystery. But research just published in The Journal of Biological Chemistry provides a few clues that may lead to breakthroughs in disease diagnosis, prevention and treatment.

Graphic rendering of chromosome

City of Hope scientists want to know how cells efficiently package DNA into chromatin (represented above). The knowledge could lead to biomarkers that give early warnings of disease or of disease risk.

Co-lead author on the study Dustin Schones, Ph.D., an assistant professor in City of Hope’s Department of Cancer Biology, explains the significance of the paper, “High Mobility Group Protein N5 (HMGN5) and Lamina-associated Polypeptide 2 (LAP2) Interact and Reciprocally Affect Their Genome-wide Chromatin Organization.”

What’s the main finding of this study?

Every cell in the human body contains a copy of the individual’s genome, the genetic blueprint that orchestrates the activities of cells for normal development and function. This genome consists of approximately 3 billion nucleotides, which is equivalent to approximately two meters of chromosomal DNA. This has to be packaged into a nucleus that is on the order of 10 microns. This packaging is analogous to approximately six miles of string being packaged into a golf ball.

This packaging is accomplished by wrapping the genome around collections of proteins to form a structure known as chromatin. The chromatin structure is subject to many chemical modifications, and aberrant modifications accompany the progression of many diseases, including cancer development.

Despite the fundamental importance of chromatin in disease, the mechanisms responsible for regulating chromatin structure remain unclear. This study attempted to further elucidate the mechanisms regulating chromatin structure by examining the genomic localization of a class of proteins that are capable of altering the chromatin architecture.

By mapping a class of chromatin architectural proteins across the genome, we identified a functional interaction between chromatin architectural proteins and lamina-associated proteins, identifying a link between chromatin and the nuclear lamin network.

What impact do you expect the study to have?

Lamina-associated proteins are commonly misregulated in cancer and are potential biomarkers for many types of cancer. By identifying an interaction between chromatin proteins and the nuclear lamin network, we have opened up new avenues for biomarker research.

What are the next steps for this line of research?

We are following this up by examining the genomic localization of other chromatin architectural proteins. We believe these experiments will allow us to better understand how the chromatin fiber interacts with the nuclear lamin network.

The study team included: Shaofei Zhang, Cedric Malicet, Mark Rochman and Michael Bustin of the National Cancer Institute; Ming Zhou of SAIC-Frederick Inc.; and Roland Foisner of the Medical University of Vienna.

This work was supported by the Center for Cancer Research, Intramural Program of the National Cancer Institute (NCI), National Institutes of Health, NCI Grant K22 HL101950, United States-Israel Binational Science Foundation Grants 2009236 and Grant P22043-B12 of the Austrian ResearchFund.