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

• Type of Material: Article
• Authors: ER Weikum, Emory University; ML Tuntland, Emory University; MN Murphy, Emory University; Eric Ortlund, Emory University
• Language: English
• Date: 2016-12-04
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Ltd
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jmb.2016.10.025
• Title of Journal or Parent Work: Journal of Molecular Biology
• ISSN: 0022-2836
• Volume: 428
• Issue: 24
• Start Page: 4981
• End Page: 4992
• Grant/Funding Information: Use of the Advanced Photon source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38.
• Keywords: nuclear receptors; CLONING; DNA-BINDING DOMAIN; GENE-EXPRESSION; germ cell nuclear factor; PROTEIN; Science & Technology; Oct4 regulation; TRANSCRIPTION FACTOR; liver receptor homolog-1; RECOGNITION; X-ray crystallography; Biochemistry & Molecular Biology; FTZ-F1; Life Sciences & Biomedicine; COMPLEX; RESPONSE ELEMENT
• Research Categories: Chemistry, Biochemistry

Abstract

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.