Credit: Graham Beards
Scientists have discovered that manipulating gene regulation can cause red blood cells to produce fetal hemoglobin, a finding that may have implications for sickle cell disease (SCD) and other hemoglobinopathies.
The researchers used protein-engineering techniques to force chromatin fiber into looped structures that contact DNA at specific sites to preferentially activate genes that regulate hemoglobin.
The team described the work in Cell. The research was previously presented at the 2013 ASH Annual Meeting.
Key to the researcher’s method is a developmental transition that normally occurs in the blood of newborns. A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin.
Hematologists have long known that SCD patients with elevated levels of fetal hemoglobin have a milder form of the disease.
“This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it,” said study author Gerd A. Blobel, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.
In previous research, his team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome. The chromatin loop that results transmits regulatory signals for specific genes.
In their current work, the researchers custom-designed zinc fingers to flip the biological switch in hematopoietic stem cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin.
The team achieved these results in cultured blood cells from adult mice and adult humans.
The researchers are now planning to test the approach in animal models of SCD. If this strategy corrects the disease in animals, it may set the stage to move to human trials.
Dr Blobel also noted that, in principle, the forced chromatin looping approach could be applied to other hemoglobin-related disorders, such as certain forms of thalassemia.
