Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin.
Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin.
复制标题
DOI：
10.1126/science.aad3312
复制
发表时间：
2016-01-15
期刊：
影响因子：
--
通讯作者：
Maeda T
中科院分区：
文献类型：
--
作者：
Masuda T;Wang X;Maeda M;Canver MC;Sher F;Funnell AP;Fisher C;Suciu M;Martyn GE;Norton LJ;Zhu C;Kurita R;Nakamura Y;Xu J;Higgs DR;Crossley M;Bauer DE;Orkin SH;Kharchenko PV;Maeda T
编码人β型珠蛋白的基因经历从胚胎到胎儿再到成人型表达的发育转换。成人形式的突变导致遗传性血红蛋白病或珠蛋白紊乱，包括镰状细胞病和地中海贫血。一些实验结果表明，这些疾病可以通过诱导胎儿型血红蛋白（HbF）来治疗。然而，抑制成人HbF的机制仍不清楚。我们发现LRF/ZBTB 7A转录因子占据胎儿γ-珠蛋白基因并维持成人γ-珠蛋白基因沉默所必需的核小体密度，并且LRF通过独立于胎儿珠蛋白阻遏物BCL 11 A的NuRD阻遏物复合物赋予其阻遏活性。我们的研究可能为血红蛋白病的治疗靶向提供额外的机会。
Genes encoding human β-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 γ-globin genes and maintains the nucleosome density necessary for γ-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.