Virginia Commonwealth University Massey Cancer Center researchers have identified the role of a protein in hemoglobin gene silencing that may one day be a potential target for the treatment of genetic blood disorders like sickle-cell anemia and beta-thalassemia on the molecular level.
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.
Unique genome architectures after fertilisation in single-cell embryos
30.03.2017 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
30.03.2017 | Health and Medicine
30.03.2017 | Health and Medicine
30.03.2017 | Medical Engineering