A Structural Investigation into Oct4 Regulation by Orphan Nuclear Receptors, Germ Cell Nuclear Factor (GCNF), and Liver Receptor Homolog-1 (LRH-1)

•Structural analysis of the pluripotency factor Oct4 regulation by NRs GCNF and LRH-1•GCNF and LRH-1 reciprocally regulate Oct4 expression by recognizing the same DNA response element•We solved the first X-ray crystal structure of GCNF, revealing its mechanism for DNA recognition.•We identified the sequence-specific DNA contacts that allow dual regulation by GCNF and LRH-1.

Oct4 is a transcription factor required for maintaining pluripotency and self-renewal in stem cells. Prior to differentiation, Oct4 must be silenced to allow for the development of the three germ layers in the developing embryo. This fine-tuning is controlled by the nuclear receptors (NRs), liver receptor homolog-1 (LRH-1) and germ cell nuclear factor (GCNF). Liver receptor homolog-1 is responsible for driving the expression of Oct4 where GCNF represses its expression upon differentiation. Both receptors bind to a DR0 motif located within the Oct4 promoter. Here, we present the first structure of mouse GCNF DNA-binding domain in complex with the Oct4 DR0. The overall structure revealed two molecules bound in a head-to-tail fashion on opposite sides of the DNA. Additionally, we solved the structure of the human LRH-1 DNA-binding domain bound to the same element. We explore the structural elements that govern Oct4 recognition by these two NRs.

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