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Publication Abstract from PubMed

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 gamma-globin -200 gene element to repress fetal haemoglobin expression. Recently, it has been reported that ZBTB7A drives primed-to-naive 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 gamma-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 naive pluripotent state in vivo. Collectively, our studies demonstrate that ZBTB7A mainly employs its ZF1-2 to recognize the PNT-associated sequence but recognizes gamma-globin -200 gene element via ZF1-4, providing insights into the molecular mechanism for the diversity of ZBTB7A's genomic localization.

ZBTB7A regulates primed-to-naive transition of pluripotent stem cells via recognition of the PNT-associated sequence by zinc fingers 1-2 and recognition of gamma-globin -200 gene element by zinc fingers 1-4.,Yang Y, Xiao L, Xue Y, Idris MO, Liu J, Pei D, Shi Y, Liao B, Li F FEBS J. 2023 Apr 4. doi: 10.1111/febs.16789. PMID:37013936^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.