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Phase separation of Ddx3xb helicase regulates maternal-to-zygotic transition in zebrafish

Cell Research volume 32, pages 715–728 (2022)Cite this article

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Abstract

Vertebrate embryogenesis involves a conserved and fundamental process, called the maternal-to-zygotic transition (MZT), which marks the switch from a maternal factors-dominated state to a zygotic factors-driven state. Yet the precise mechanism underlying MZT remains largely unknown. Here we report that the RNA helicase Ddx3xb in zebrafish undergoes liquid–liquid phase separation (LLPS) via its N-terminal intrinsically disordered region (IDR), and an increase in ATP content promotes the condensation of Ddx3xb during MZT. Mutant form of Ddx3xb losing LLPS ability fails to rescue the developmental defect of Ddx3xb-deficient embryos. Interestingly, the IDR of either FUS or hnRNPA1 can functionally replace the N-terminal IDR in Ddx3xb. Phase separation of Ddx3xb facilitates the unwinding of 5’ UTR structures of maternal mRNAs to enhance their translation. Our study reveals an unprecedent mechanism whereby the Ddx3xb phase separation regulates MZT by promoting maternal mRNA translation.

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Fig. 1: Zebrafish Ddx3xb forms liquid–liquid phase separation via its N-terminal IDR.
Fig. 2: An increase in ATP concentration promotes both exogenous and endogenous phase separation of zebrafish Ddx3xb.
Fig. 3: Ddx3xb phase separation is essential for zebrafish early embryogenesis.
Fig. 4: Ddx3xb phase separation facilitates zebrafish MZT.
Fig. 5: Condensation of Ddx3xb regulates maternal mRNA translation via unwinding RNA structures.
Fig. 6: Ddx3xb regulates maternal mRNA translation in a condensation-dependent manner.
Fig. 7: Schematic model showing that Ddx3xb regulates maternal mRNA translation efficiency in a condensation-dependent manner.

Data availability

The RNA-seq, RIP, and ribosome profiling data supporting the conclusions of this article have been deposited in the Gene Expression Omnibus database (GEO: GSE169169), and also the Genome Sequence Archive (GSA: CRA003999 linked to the BioProject with accession Number PRJCA004602).

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Funding

This work was supported by grants from the National Natural Science Foundation of China (32030058, 32121001, 31625016, 32030032), the Strategic Priority Research Program of the Chinese Academy of Sciences, China (XDA16010207, XDA16010501, XDPB2004), the National Key R&D Program of China (2018YFA0800200, 2019YFA0110901), the Youth Innovation Promotion Association of Chinese Academy of Sciences (2018133), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences (2019RU003).

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Author notes

  1. Boyang Shi

    Present address: Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

  2. These authors contributed equally: Boyang Shi, Jian Heng, Jia-Yi Zhou, Ying Yang.

Authors and Affiliations

  1. CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Boyang Shi, Jia-Yi Zhou, Ying Yang, Wan-Ying Zhang, Yong-Liang Zhao & Yun-Gui Yang

  2. China National Center for Bioinformation, Beijing, China

    Boyang Shi, Jia-Yi Zhou, Ying Yang, Wan-Ying Zhang, Yong-Liang Zhao & Yun-Gui Yang

  3. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Jian Heng & Feng Liu

  4. Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China

    Jian Heng, Ying Yang, Feng Liu & Yun-Gui Yang

  5. University of Chinese Academy of Sciences, Beijing, China

    Jia-Yi Zhou, Ying Yang, Wan-Ying Zhang, Yong-Liang Zhao, Feng Liu & Yun-Gui Yang

  6. Chinese Institute for Brain Research, Beijing, China

    Magdalena J. Koziol

  7. Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China

    Pilong Li

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Contributions

Y.-G.Y. and F.L. conceived this project, supervised the study; B.S., J.H. and Y.Y. performed the experiments; J.-Y.Z., B.S. and W.-Y.Z. performed bioinformatics analysis; Y.-G.Y., F.L., M.J.K., P.L., Y.-L.Z., Y.Y., J.-Y.Z., J.H. and B.S. discussed and integrated the data, wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Feng Liu or Yun-Gui Yang.

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Shi, B., Heng, J., Zhou, JY. et al. Phase separation of Ddx3xb helicase regulates maternal-to-zygotic transition in zebrafish. Cell Res 32, 715–728 (2022). https://doi.org/10.1038/s41422-022-00655-5

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