生物
基因沉默
胎儿血红蛋白
清脆的
珠蛋白
遗传学
基因
转录因子
分子生物学
细胞生物学
胎儿
怀孕
作者
Kunhua Qin,Peng Huang,Ruopeng Feng,Cheryl A. Keller,Scott A. Peslak,Eugene Khandros,Megan S. Saari,Xianjiang Lan,Thiyagaraj Mayuranathan,Phillip A. Doerfler,Osheiza Abdulmalik,Belinda Giardine,Stella T. Chou,Junwei Shi,Ross C. Hardison,Mitchell J. Weiss,Gerd A. Blobel
出处
期刊:Nature Genetics
[Springer Nature]
日期:2022-05-26
卷期号:54 (6): 874-884
被引量:14
标识
DOI:10.1038/s41588-022-01076-1
摘要
The mechanisms by which the fetal-type β-globin-like genes HBG1 and HBG2 are silenced in adult erythroid precursor cells remain a fundamental question in human biology and have therapeutic relevance to sickle cell disease and β-thalassemia. Here, we identify via a CRISPR–Cas9 genetic screen two members of the NFI transcription factor family—NFIA and NFIX—as HBG1/2 repressors. NFIA and NFIX are expressed at elevated levels in adult erythroid cells compared with fetal cells, and function cooperatively to repress HBG1/2 in cultured cells and in human-to-mouse xenotransplants. Genomic profiling, genome editing and DNA binding assays demonstrate that the potent concerted activity of NFIA and NFIX is explained in part by their ability to stimulate the expression of BCL11A, a known silencer of the HBG1/2 genes, and in part by directly repressing the HBG1/2 genes. Thus, NFI factors emerge as versatile regulators of the fetal-to-adult switch in β-globin production. NFIA and NFIX directly repress the expression of fetal-type β-globin-like genes HBG1 and HBG2 in adult erythroid cells, and also do it indirectly through the upregulation of BCL11A.
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