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

来源：

BLOOD | 2013年 / 121卷 / 17期

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

页码：3493 / 3501

页数：9