Publication Date:
2008-12-06
Description:
Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-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 beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- HL32259-27/HL/NHLBI NIH HHS/ -- HL32262-26/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2008 Dec 19;322(5909):1839-42. doi: 10.1126/science.1165409. Epub 2008 Dec 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology/Oncology, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19056937" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Carrier Proteins/*genetics/metabolism
;
Cell Line, Tumor
;
Cells, Cultured
;
Down-Regulation
;
Erythroblasts/metabolism
;
Erythroid Cells/*metabolism
;
Erythroid Precursor Cells/metabolism
;
Erythropoiesis
;
Fetal Hemoglobin/biosynthesis/*genetics
;
GATA1 Transcription Factor/metabolism
;
*Gene Expression Regulation
;
Hemoglobinopathies/therapy
;
Histone Deacetylases/metabolism
;
Humans
;
K562 Cells
;
Mi-2 Nucleosome Remodeling and Deacetylase Complex
;
Mice
;
Multigene Family
;
Nuclear Proteins/*genetics/metabolism
;
Polymorphism, Single Nucleotide
;
Protein Isoforms/genetics/metabolism
;
RNA Interference
;
Transcription Factors/metabolism
;
Transcription, Genetic
;
beta-Globins/genetics/metabolism
;
gamma-Globins/genetics/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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