Epigenetics of beta-globin gene regulation.
ABSTRACT It is widely recognized that the next great challenge in the post-genomic period is to understand how the genome establishes the cell and tissue specific patterns of gene expression that underlie development. The beta-globin genes are among the most extensively studied tissue specific and developmentally regulated genes. The onset of erythropoiesis in precursor cells and the progressive expression of different members of the beta-globin family during development are accompanied by dramatic epigenetic changes in the locus. In this review, we will consider the relationship between histone and DNA modifications and the transcriptional activity of the beta-globin genes, the dynamic changes in epigenetic modifications observed during erythroid development, and the potential these changes hold as new targets for therapy in human disease.
Article: Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia.[show abstract] [hide abstract]
ABSTRACT: We have previously demonstrated that 5-aza-2'-deoxycytidine (decitabine) augments fetal hemoglobin (HbF) levels in patients with sickle cell anemia (SS) who did not respond to hydroxyurea (HU). The present study was designed to determine the effect of repeated decitabine dosing on HbF levels and hematologic toxicity over a 9-month treatment period. Seven patients (5 HU nonresponders) were entered. One patient had alpha-thalassemia sickle cell anemia. Decitabine was administered by intravenous infusion at a starting dose of 0.3 mg/kg per day, 5 days a week for 2 weeks, followed by a 4-week observation period. If the absolute neutrophil count dropped below 1000, the dose was reduced by 0.05 mg/kg per day in the next cycle. A drug dose was obtained for each patient, and it resulted in an elevated HbF without neutropenia (absolute neutrophil count nadir greater than 1500) or evidence of cumulative toxicity. Average HbF and average maximal HbF levels attained during the last 20 weeks of treatment for the 6 SS patients increased to 13.93% +/- 2.75% and 18.35% +/- 4.46%, respectively, from a pretreatment mean of 3.12% +/- 2.75%. Mean and mean maximal hemoglobin (Hb) levels increased from 7.23 +/- 2.35 g/dL to 8.81 +/- 0.42 g/dL and 9.73 +/- 0.53 g/dL, respectively. Individual maximal F-cell number observed during the trial was 69% +/- 10.12%. The absence of cumulative toxicity may allow shorter intervals between drug treatments, which may lead to higher hemoglobin and HbF levels after several treatment cycles and, therefore, to greater clinical improvement.Blood 07/2002; 99(11):3905-8. · 9.90 Impact Factor
Genes & Development 11/1999; 13(19):2465-77. · 11.66 Impact Factor
Article: Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken beta-globin chromosomal domain.[show abstract] [hide abstract]
ABSTRACT: The distribution of core histone acetylation across the chicken beta-globin locus has been mapped in 15 day chicken embryo erythrocytes by immunoprecipitation of mononucleosomes with an antibody recognizing acetylated histones, followed by hybridization probing at several points in the locus. A continuum of acetylation was observed, covering both genes and intergenic regions. Using the same probes, the generalized sensitivity to DNase I was mapped by monitoring the disappearance of intact genomic restriction fragments from Southern transfers. Close correspondence between the 33 kb of sensitive chromatin and the extent of acetylation indicates that one role of the modification could be the generation and/or maintenance of the open conformation. The precision of acetylation mapping makes it a possible approach to the definition of chromosomal domain boundaries.The EMBO Journal 05/1994; 13(8):1823-30. · 9.20 Impact Factor