Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

被引：269

作者：

Masuda, Takeshi ^{[1
]}

Wang, Xin ^{[2
]}

Maeda, Manami ^{[1
]}

Canver, Matthew C. ^{[3
]}

Sher, Falak ^{[3
]}

Funnell, Alister P. W. ^{[4
]}

Fisher, Chris ^{[5
]}

Suciu, Maria ^{[5
]}

Martyn, Gabriella E. ^{[4
]}

Norton, Laura J. ^{[4
]}

Zhu, Catherine ^{[1
]}

Kurita, Ryo ^{[6
]}

Nakamura, Yukio ^{[6
,7
]}

Xu, Jian ^{[3
,8
]}

Higgs, Douglas R. ^{[5
]}

Crossley, Merlin ^{[4
]}

Bauer, Daniel E. ^{[3
]}

Orkin, Stuart H. ^{[3
,9
]}

Kharchenko, Peter V. ^{[2
]}

Maeda, Takahiro ^{[1
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Hematol,Dept Med, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Div Hematol Oncol, Dept Pediat Oncol,Dana Farber Canc Inst,Boston Ch, Boston, MA 02115 USA

[4] Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia

[5] Univ Oxford, Weatherall Inst Mol Med, Med Res Council, Mol Haematol Unit, Oxford, England

[6] RIKEN BioResource Ctr, Cell Engn Div, Tsukuba, Ibaraki, Japan

[7] Univ Tsukuba, Comprehens Human Sci, Tsukuba, Ibaraki, Japan

[8] Univ Texas SW Med Ctr Dallas, Dept Pediat, Childrens Res Inst, Dallas, TX 75390 USA

[9] Brigham & Womens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA

来源：

SCIENCE | 2016年 / 351卷 / 6270期

基金：

美国国家科学基金会;

关键词：

GAMMA-GLOBIN GENE; ERYTHROBLASTS; PROTEINS; MICE;

D O I：

10.1126/science.aad3312

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：

Genes encoding human beta-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal g-globin genes and maintains the nucleosome density necessary for g-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies.

引用

页码：285 / 289

页数：5

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