Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells

被引:78
作者
Amaya, Maria [1 ,2 ]
Desai, Megha [1 ,3 ]
Gnanapragasam, Merlin Nithya [1 ,3 ]
Wang, Shou Zhen [1 ]
Zhu, Sheng Zu [1 ]
Williams, David C., Jr. [1 ,4 ]
Ginder, Gordon D. [1 ,2 ,3 ,5 ]
机构
[1] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA
[3] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA 23298 USA
[4] Virginia Commonwealth Univ, Dept Pathol, Richmond, VA 23298 USA
[5] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA
基金
美国国家卫生研究院;
关键词
CHROMATIN REMODELER MI-2-BETA; YAC TRANSGENIC MICE; KRUPPEL-LIKE FACTOR; TRANSCRIPTION FACTOR; DNA METHYLATION; HEMOGLOBIN PRODUCTION; HISTONE DEACETYLASE; BINDING-PROTEINS; BETA-THALASSEMIA; EXPRESSION;
D O I
10.1182/blood-2012-11-466227
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate beta-type globin gene disorders such as sickle cell anemia and beta-thalassemia through activation of the fetal gamma-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in gamma-globin gene silencing, and Mi2 beta (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2 beta relieves gamma-globin gene silencing in beta-YAC transgenic murine chemical inducer of dimerization hematopoietic cells and in CD34(+) progenitor-derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2 beta binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for gamma-globin gene silencing during beta-type globin gene switching. Remarkably, <50% knockdown of Mi2 beta is sufficient to significantly induce gamma-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2 beta is a potential target for therapeutic induction of fetal hemoglobin.
引用
收藏
页码:3493 / 3501
页数:9
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