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

被引：698

作者：

Sankaran, Vijay G. ^{[1
,2
]}

Menne, Tobias F. ^{[1
]}

Xu, Jian ^{[1
]}

Akie, Thomas E. ^{[1
]}

Lettre, Guillaume ^{[3
,4
,5
]}

Van Handel, Ben ^{[6
]}

Mikkola, Hanna K. A. ^{[6
]}

Hirschhorn, Joel N. ^{[3
,4
,5
]}

Cantor, Alan B. ^{[1
]}

Orkin, Stuart H. ^{[1
,2
,7
]}

机构：

[1] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston,Harvard Stem Cell Inst, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[4] Childrens Hosp, Div Genet Endocrinol, Boston, MA 02115 USA

[5] Childrens Hosp, Program Genom, Boston, MA 02115 USA

[6] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA

[7] Howard Hughes Med Inst, Boston, MA 02115 USA

来源：

SCIENCE | 2008年 / 322卷 / 5909期

关键词：

D O I：

10.1126/science.1165409

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1839 / 1842

页数：4

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