The Human Genome Project inspired hope that mapping the human DNA sequence would dramatically accelerate the process of identifying drug targets and developing diagnostic tools. That hasn’t generally happened—largely because of the fact that although a person’s genes are almost identical throughout their body, the genes that code protein sequences are interpreted differently in different parts of the body and under diverse physiological conditions.
This makes proteomics––the study of the protein structures and functions in an organism, tissue, or cell–– an important area of research. Protein function is controlled by many factors and can be dictated by the distinct array of modifications that occur after proteins are synthesized. Modifications that are unique to specific diseases can inform about the origin of the disease and provide a platform for designing treatment strategies.
Yingming Zhao, PhD, professor in the Ben May Department of Cancer Research at the University of Chicago, and his team focus their work on post-translational modifications (PTMs), which are associated with a majority of diseases and almost all cellular pathways. The researchers are charting new territory in the understanding of post-translational modifications by describing novel “marks” on histones and metabolic enzymes.
Histones are the protein components of nucleosomes upon which DNA is wound and compacted in the nucleus in chromatin. A wide array of histone modifications, or histone marks, has been identified, and their presence or absence alters the accessibility of genes to the transcriptional machinery and subsequent gene expression. The dysregulation of histone marks has been linked with diverse physiological conditions and diseases, such as cancer, neurodegenerative disorders, and autoimmune diseases.
Frequently, tumor cells have different levels or patterns of histone marks compared to their normal cell counterparts. Not only can these modifications serve as biomarkers of cancer, but they also may provide therapeutic opportunities, as there are drugs available that prevent many of these marks from forming.
In a collaborative study published in the most recent issue of Cell with the title of “SnapShot: Histone Modifications,” Zhao comprehensively summarized about 400 histone marks, including more than 200 histone marks identified by his group. Some of these newly discovered modifications may serve as biological markers for controlling gene expression and contribute toward our understanding of dysregulations that occur in cancer.
“If we want to understand epigenetic mechanisms and their role in diseases, such as cancer, it is critical for us to have a complete understanding of histone marks, a cell’s regulatory elements for epigenetic programming,” said Zhao.
Other researchers on the study were Dr. He Huang of the University of Chicago, Dr. Benjamin A. Garcia of the University of Pennsylvania, and Benjamin R. Sabari and Dr. C. David Allis, both of the Rockefeller University.