In the April issue of the journal Proceedings of the National Academy of Sciences, researchers reported for the first time that the protein, MBD2, mediates silencing of the fetal gamma-globin gene through DNA methylation, a process that chemically modifies DNA. Researchers used a transgenic mouse model containing the human hemoglobin gene locus to show that MBD2 interprets the DNA methylation "signal" throughout the genome, which determined how the pattern of methylation effected the expression of specific genes.
"Understanding how these epigenetic switches turn specific genes on and off, and identifying the important proteins involved, could lead to more targeted ways to reactivate genes and determine if there is a therapeutic benefit for particular diseases," said Gordon D. Ginder, M.D., director of the VCU Massey Cancer Center and lead author of the study.
Epigenetics refers to the study of the modifications of DNA and the surrounding proteins found in chromosomes that turn genes on and off and that can be passed on after cell division in an individual. Traditionally, researchers have focused their attention on changes to the DNA base code as being responsible for altered gene expression in disease.
Previous clinical studies have shown that increased gamma-globin gene expression has a positive effect in those with sickle-cell anemia or beta-thalassemia. "The gamma-globin genes normally become silent in adult hemoglobin expressing red blood cells. If we can find a specific and safe mechanism to reactivate the gamma-globin gene, we may be able to overcome the underlying molecular defect in sickle-cell anemia and beta-thalassemia," Ginder said.
Gene silencing is important for the differentiation of many different types of cells to take place. In humans, there are five beta-type globin genes clustered on chromosome 11 in the order in which they are "turned on," or expressed, during development. These genes include the embryonic epsilon-globin gene, two gamma-globin genes and the adult delta- and beta-globin genes. During fetal development, the embryonic epsilon-globin gene is active first, followed by the gamma-globin genes, and finally the major adult form, beta-globin, becomes the dominant expressed gene following birth.
According to Ginder, regulation of many genes and other molecular processes require DNA methylation. He said that DNA methylation is associated with the silencing of many types of genes, including tumor suppressor genes found in cancer cells. Scientists now know that DNA methylation plays a significant role in the development and progression of several forms of cancer.
Currently, the only therapeutic approach to relieving methylation-mediated gene silencing that has been tested in humans is through blocking the methylating enzymes non-specifically throughout the cell. Although this approach may have the desired effect on the specific gene or genes involved, it can also have an undesirable effect by turning on the wrong genes, he said.
"The more targeted the approach the better, because there is less likelihood of producing any unintended negative side-effects. For example, there is some specificity of how some proteins, such as MBD2, act to silence only certain sets of methylated genes," Ginder said.
Mutations of hemoglobin genes play a role in genetic blood disorders such as sickle-cell anemia and beta-thalassemia.
This work was supported by a grant from the National Institutes of Health.
Ginder collaborated with VCU Massey Cancer Center researchers Jeremy W. Rupon, B.S., a combined M.D./Ph.D. student; Shou Zhen Wang, M.S., a research associate; and Joyce Lloyd, Ph.D., an associate professor of human genetics. Also Karin Gaensler, Ph.D., from the University of California collaborated on this work.
About the VCU Massey Cancer Center: The VCU Massey Cancer Center, one of 61 National Cancer Institute-designated research institutions, is VCU's focal point for basic and clinical cancer research, education, prevention and cancer health care. Since 1975, Massey has served as an internationally recognized center of excellence. Its 175 doctors and researchers are dedicated to improving the quality of human life by developing effective means to prevent, control and ultimately to cure cancer. Visit Massey online at www.massey.vcu.edu.
Journal
Proceedings of the National Academy of Sciences