Submitted February 22, 2007
Accepted July 7, 2007
Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin
Hassana Fathallah*, Rona S Weinberg, Yelena Galperin, Millicent Sutton, and George F Atweh
Divsion of Hematology & Medical Oncology, Mount Sinai School of Medicine, New York, NY, United States
Clinical Services, New York Blood Center, New York, NY, United States
* Corresponding author; email: hassana.fathallah{at}mssm.edu.
Butyrate is a prototype of histone deacetylase inhibitors that is believed to reactivate silent genes by inducing epigenetic modifications. Although butyrate was shown to induce fetal hemoglobin (HbF) production in patients with hemoglobin disorders, the mechanism of this induction has not been fully elucidated. Our studies of the epigenetic configuration of the 
-globin cluster suggest that DNA methylation and histone H3 acetylation are important for the regulation of developmental stage-specific expression of the -like globin genes, while acetylation of both histones H3 and H4 appear to be important for the regulation of tissue-specific expression. These studies suggest that DNA methylation may be important for the silencing of the -like globin genes in non-erythroid hematopoietic cells but may not be necessary for their silencing in non-hematopoietic cells. Furthermore, our studies demonstrate that butyrate exposure results in a true reversal of the normal developmental switch from 
- to -globin expression. This is associated with increased histone acetylation and decreased DNA methylation of the -globin genes with opposite changes in the -globin gene. These studies provide strong support for the role of epigenetic modifications in the normal developmental and tissue-specific regulation of globin gene expression and in the butyrate-mediated pharmacological induction of HbF production.
