Correction of Sickle Cell Disease in Adult Mice by Interference with Fetal Hemoglobin Silencing
by Cassandra Mathers
Sickle cell disease is a genetic disorder that affects adult hemoglobin, and causes many problems within the body. Normal adult hemoglobin (HbA) is a protein found in high concentrations in red blood cells. This protein binds gases such as oxygen and carbon dioxide and transports them to and from the tissues of the body. It is made of four protein chains. When an amino acid in one of the chains of hemoglobin is substituted with another amino acid, a destructive mutation occurs. This type of hemoglobin, called Hbs, forms a “water hating”, or hydrophobic, pocket among other Hbs chains, and causes the proteins to stick together. When they stick together, the red blood cell folds in on itself and loses it ability to hold oxygen and carbon dioxide. When the body develops, fetal hemoglobin (HbF) is formed first, which is a different type of protein, and then the transition to adult hemoglobin occurs. A new study has shown that if the transition from fetal hemoglobin to adult hemoglobin is silenced, the effects of sickle cell disease can be reversed.
Scientists used adult mice to show that the inactivation of a transcription factor, BCL11A, corrects the effects of sickle cell disease. A transcription factor is a protein that binds to DNA and controls the production of proteins. BCL11A is one factor that regulates fetal hemoglobin. If this factor is removed, fetal hemoglobin is not silenced and continues to be produced. If HbF is being produced, adult hemoglobin is not produced, and therefore a mutation in the protein chains of the adult hemoglobin cannot occur. One problem associated with the silencing of the transcription factor is side effects it could have on the cell. However, scientists were able to show that BCL11A is selective in its targets in red blood cells and only affects the DNA that produces the protein for hemoglobin.
In addition to its effect on the transcription of DNA, BCL11A has an influence on other pathways that influence the control of fetal hemoglobin. DNA methylation and histone deacetylation are two pathways that inhibit other components of the cell. As a result of the inhibition, the reactivation of fetal hemoglobin can occur. Scientists found that when BCL11A was removed from the cell, these two pathways were enhanced, which led to an even higher reactivation of fetal hemoglobin in the adult mice.
All of the evidence found in this study heavily supports the manipulation of the transcription factor BCL11A to reverse sickle cell disease. When BCL11A-null alleles (alleles not containing BCL11A) were introduced to mice that had sickle cell disease, the number of red blood cells, and the amount of hemoglobin within these cells increased. The survival rate of these cells also increased. In order to make sure these effects were directly from the types of alleles that were introduced, a stain specific for fetal hemoglobin blood cells was used. This stain showed a high amount of HbF in mice given the special BCL11A-null alleles and a low HbF count in mice not given the alleles.
Future research will look into the specific strategies for interfering with BCL11A expression. There are many strategies proposed, including deletion of the BCL11A mRNA, screening for small molecules that inhibit BCL11A, or the disruption of protein interactions. Sickle cell disease is a destructive disease that causes fatigue, severe pain, and potential loss of important organs such as the spleen and kidney. If this transcription factor research can be used in humans and the effects are similar as that in mice, the sickle cell disease could potentially be cured and eliminated from the population.
Xu, J., Peng, C., Sankaran, V. G. & Shao, Z., et al. (2011, October 13). Science Express.