Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A

• Published in: Science (American Association for the Advancement of Science) 2008-12, Vol.322 (5909), p.1839-1842
• Main Authors: Sankaran, Vijay G, Menne, Tobias F, Xu, Jian, Akie, Thomas E, Lettre, Guillaume, Van Handel, Ben, Mikkola, Hanna K.A, Hirschhorn, Joel N, Cantor, Alan B, Orkin, Stuart H
• Format: Article
• Language: English
• Subjects: Anemias. Hemoglobinopathies; Animals; beta-Globins - genetics; beta-Globins - metabolism; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; Cell lines; Cells, Cultured; Diseases of red blood cells; Down-Regulation; Erythroblasts; Erythroblasts - metabolism; Erythroid cells; Erythroid Cells - metabolism; Erythroid Precursor Cells - metabolism; Erythropoiesis; Fetal Hemoglobin - biosynthesis; Fetal Hemoglobin - genetics; Fundamental and applied biological sciences. Psychology; gamma-Globins - genetics; gamma-Globins - metabolism; GATA1 Transcription Factor - metabolism; Gene expression; Gene Expression Regulation; Genes; Genetic loci; Genotype & phenotype; Hematologic and hematopoietic diseases; Hematology; Hemoglobinopathies - therapy; Hemoglobins; Histone Deacetylases - metabolism; Humans; K562 Cells; Medical research; Medical sciences; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Mice; Molecular and cellular biology; Molecular genetics; Multigene Family; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Polymorphism, Single Nucleotide; Protein isoforms; Protein Isoforms - genetics; Protein Isoforms - metabolism; RNA Interference; Sickle cell disease; Small interfering RNA; Transcription Factors - metabolism; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1165409

Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the β-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high-HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the β-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in β-hemoglobin disorders.