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Forced chromatin looping may reprogram gene expression in hemoglobinopathy
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Forced chromatin looping activated the silenced murine embryonic beta-h1-globin gene and the human fetal gamma-globin gene in adult erythroid cells, demonstrating its potential as a new treatment for patients with hemoglobinopathies, according to study results presented at the ASH Annual Meeting and Exposition.
“Augmented levels of fetal hemoglobin are very therapeutic for patients with hemoglobinopathies,” Jeremy W. Rupon, MD, PhD, of the division of hematology at the Children’s Hospital of Philadelphia, said during a press conference. “We’re showing here a novel approach, because for the first time, we can manipulate the higher order chromatin structure within erythroid cells to overcome developmental expression patterns.”
Rupon and colleagues found that a zinc finger protein used to tether the looping factor Ldb1 to the murine embryonic beta-h1 promoter is able to overcome developmental silencing of this gene in adult erythroid cells. They observed up to an 800-fold increase in beta-h1 transcription, representing nearly 30% of total beta-globin expression.
Further genetic studies elucidated that the activity of the zinc finger-Ldb1 protein was dependent upon formation of a long-range looped contact between the beta-h1 promoter and a distal enhancer.
Using a similar approach to target the promoter of the fetal gamma-globin in adult human erythroid cells, they observed strong induction of gamma-globin expression, accounting for close to 90% of total beta-type globin transcription.
In addition, they observed a reduction in beta-globin transcription, supporting a model in which the enhancer is directed toward the fetal gene at the expense of the adult gene.
These results suggest a possible novel approach to augment gamma-globin expression with potential application for patients with hemoglobinopathies, Rupon and colleagues concluded.
“We have opened up a new potential therapeutic avenue by forcing chromatin loops to increase fetal hemoglobin production so it overtakes existing mutated adult hemoglobin,” primary investigator Gerd Blobel, MD, PhD, of the University of Pennsylvania, said in a press release. “There is a tremendous interest in this field to raise fetal globin genes in people who have sickle cell disease or certain forms of beta-thalassemia, which can significantly improve their condition.”
For more information:
Rupon JW. Abstract #433. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10; New Orleans.
Disclosure: The researchers report employment with Sangamo BioSciences.