A pair of transcription factors repress the expression of fetal hemoglobin and might therefore be targets for the treatment of hemoglobinopathies, according to research published in Science.
Previous studies have indicated that hemoglobinopathies may be treated by inducing fetal-type hemoglobin.
However, researchers have been unable to achieve this because they don’t fully understand the factors that influence adult hemoglobin, including those that repress fetal hemoglobin.
Takeshi Masuda, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues suspected that the transcription factor LRF might play a role in the differentiation between hemoglobin types.
To test this theory, the team knocked out the gene that encodes LRF, ZBTB7A, in mice.
This boosted the expression of genes known to play a role in the production of fetal-type hemoglobin but not adult-type hemoglobin. Knocking out ZBTB7A in human cells produced similar results.
The researchers said LRF/ZBTB7A occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults.
They also discovered that LRF represses the expression of fetal-type hemoglobin through a NuRD repressor complex independent of BCL11A, a transcription factor already known to repress fetal-type hemoglobin.
However, in mice with both ZBTB7A and BCL11A knocked out, fetal-type hemoglobin represented a greater percentage of total hemoglobin (91% to 94%) than when either gene was knocked out alone.
Therefore, the researchers believe that therapies targeting the 2 proteins these genes express—LRF and BCL11A—may offer a viable way to induce fetal-type hemoglobin in patients with hemoglobinopathies.
