锌指
生物
锌
遗传学
基因
珠蛋白
诱导多能干细胞
序列(生物学)
干细胞
识别序列
分子生物学
细胞生物学
转录因子
计算生物学
胚胎干细胞
化学
限制性酶
有机化学
作者
Yang Yang,Lizhan Xiao,Yanting Xue,Mukhtar Oluwaseun Idris,Jing Liu,Duanqing Pei,Yunyu Shi,Baojian Liao,Fudong Li
出处
期刊:FEBS Journal
[Wiley]
日期:2023-04-14
卷期号:290 (15): 3896-3909
摘要
ZBTB7A, a transcription factor containing a tandem array of four Cys2-His2 zinc fingers (ZFs), is vital for multiple physiological events through directional binding to different genomic loci. Our previously determined crystal structure of ZBTB7A in complex with a GCCCCTTCCCC sequence revealed that all four ZFs (ZF1-4) are involved in binding to γ-globin -200 gene element to repress fetal haemoglobin expression. Recently, it has been reported that ZBTB7A drives primed-to-naïve transition (PNT) of pluripotent stem cells through binding to a 12-bp consensus sequence ([AAGGACCCAGAT], referred to as PNT-associated sequence). Here, we report a crystal structure of ZBTB7A ZF1-3 in complex with the PNT-associated sequence. The structure shows that ZF1 and ZF2 primarily contribute to recognizing the GACCC core sequence mimicking the half part (GCCCC) of γ-globin -200 gene element via specific hydrogen bonding and van der Waals contacts. The mutations of key residues in ZF1-2 remarkably reduce their binding affinities for the PNT-associated sequence in vitro and cannot restore epiblast stem cells to the naïve pluripotent state in vivo. Collectively, our studies demonstrate that ZBTB7A mainly employs its ZF1-2 to recognize the PNT-associated sequence but recognizes γ-globin -200 gene element via ZF1-4, providing insights into the molecular mechanism for the diversity of ZBTB7A's genomic localization.
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