Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition
Kobayashi W, Sappler AH, Bollschweiler D, Kümmecke M, Basquin J, Arslantas EN, Ruangroengkulrith S, Hornberger R, Duderstadt K, Tachibana K. 2024. Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition. Nature Structural & Molecular Biology. 31, 757–766.
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Author
Kobayashi, Wataru;
Sappler, Anna H.;
Bollschweiler, Daniel;
Kümmecke, Maximilian;
Basquin, Jérôme;
Arslantas, Eda NurISTA;
Ruangroengkulrith, Siwat;
Hornberger, Renate;
Duderstadt, Karl;
Tachibana, Kikuë
Abstract
Gene expression during natural and induced reprogramming is controlled by pioneer transcription factors that initiate transcription from closed chromatin. Nr5a2 is a key pioneer factor that regulates zygotic genome activation in totipotent embryos, pluripotency in embryonic stem cells and metabolism in adult tissues, but the mechanism of its pioneer activity remains poorly understood. Here, we present a cryo-electron microscopy structure of human NR5A2 bound to a nucleosome. The structure shows that the conserved carboxy-terminal extension (CTE) loop of the NR5A2 DNA-binding domain competes with a DNA minor groove anchor of the nucleosome and releases entry-exit site DNA. Mutational analysis showed that NR5A2 D159 of the CTE is dispensable for DNA binding but required for stable nucleosome association and persistent DNA ‘unwrapping’. These findings suggest that NR5A2 belongs to an emerging class of pioneer factors that can use DNA minor groove anchor competition to destabilize nucleosomes and facilitate gene expression during reprogramming.
Publishing Year
Date Published
2024-05-01
Journal Title
Nature Structural & Molecular Biology
Publisher
Springer Nature
Acknowledgement
We are very grateful to K. Abe, L. G. Hernandez, C. Kobayashi, K. Straßer and M. Zaczek for their contributions and technical support. We thank N. Thomä for advice on SeEN-seq. We are grateful to A. Musacchio for insightful discussions. We thank J.-M. Peters for critical reading of the manuscript and all members of K.T.’s laboratory for discussions. We thank T. Schäfer at the cryo-EM facility for assistance in cryo-EM data collection, and R. H. Kim for sequencing at the NGS facility, MPIB. K.T. is an Honorary Professor at the Department of Biology, Ludwig-Maximilians-University, Munich. Funding: European Research Council grant ERC-CoG-818556 TotipotentZygotChrom (K.T.). European Research Council grant ERC-StG-804098 ReplisomeBypass (K.D.). Max Planck Society (K.T., K.D.).
Volume
31
Page
757-766
ISSN
eISSN
IST-REx-ID
Cite this
Kobayashi W, Sappler AH, Bollschweiler D, et al. Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition. Nature Structural & Molecular Biology. 2024;31:757-766. doi:10.1038/s41594-024-01239-0
Kobayashi, W., Sappler, A. H., Bollschweiler, D., Kümmecke, M., Basquin, J., Arslantas, E. N., … Tachibana, K. (2024). Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition. Nature Structural & Molecular Biology. Springer Nature. https://doi.org/10.1038/s41594-024-01239-0
Kobayashi, Wataru, Anna H. Sappler, Daniel Bollschweiler, Maximilian Kümmecke, Jérôme Basquin, Eda Nur Arslantas, Siwat Ruangroengkulrith, Renate Hornberger, Karl Duderstadt, and Kikuë Tachibana. “Nucleosome-Bound NR5A2 Structure Reveals Pioneer Factor Mechanism by DNA Minor Groove Anchor Competition.” Nature Structural & Molecular Biology. Springer Nature, 2024. https://doi.org/10.1038/s41594-024-01239-0.
W. Kobayashi et al., “Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition,” Nature Structural & Molecular Biology, vol. 31. Springer Nature, pp. 757–766, 2024.
Kobayashi W, Sappler AH, Bollschweiler D, Kümmecke M, Basquin J, Arslantas EN, Ruangroengkulrith S, Hornberger R, Duderstadt K, Tachibana K. 2024. Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition. Nature Structural & Molecular Biology. 31, 757–766.
Kobayashi, Wataru, et al. “Nucleosome-Bound NR5A2 Structure Reveals Pioneer Factor Mechanism by DNA Minor Groove Anchor Competition.” Nature Structural & Molecular Biology, vol. 31, Springer Nature, 2024, pp. 757–66, doi:10.1038/s41594-024-01239-0.
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