OBOX regulates mouse zygotic genome activation and early development

Shuyan Ji, Fengling Chen, Paula Stein, Jiacheng Wang, Ziming Zhou, Lijuan Wang, Qing Zhao, Zili Lin, Bofeng Liu, Kai Xu, Fangnong Lai, Zhuqing Xiong, Xiaoyu Hu, Tianxiang Kong, Feng Kong, Bo Huang, Qiujun Wang, Qianhua Xu, Qiang Fan, Ling Liu, Carmen J. Williams, Richard M. Schultz () and Wei Xie ()
Additional contact information
Shuyan Ji: Tsinghua University
Fengling Chen: Tsinghua University
Paula Stein: National Institutes of Health
Jiacheng Wang: Tsinghua University
Ziming Zhou: Tsinghua University
Lijuan Wang: Tsinghua University
Qing Zhao: Tsinghua University
Zili Lin: Tsinghua University
Bofeng Liu: Tsinghua University
Kai Xu: Tsinghua University
Fangnong Lai: Tsinghua University
Zhuqing Xiong: Tsinghua University
Xiaoyu Hu: Tsinghua University
Tianxiang Kong: Tsinghua University
Feng Kong: Tsinghua University
Bo Huang: Zhejiang University School of Medicine
Qiujun Wang: Tsinghua University
Qianhua Xu: Tsinghua University
Qiang Fan: Tsinghua University
Ling Liu: Tsinghua University
Carmen J. Williams: National Institutes of Health
Richard M. Schultz: University of Pennsylvania
Wei Xie: Tsinghua University

Nature, 2023, vol. 620, issue 7976, 1047-1053

Abstract: Abstract Zygotic genome activation (ZGA) activates the quiescent genome to enable the maternal-to-zygotic transition1,2. However, the identity of transcription factors that underlie mammalian ZGA in vivo remains elusive. Here we show that OBOX, a PRD-like homeobox domain transcription factor family (OBOX1–OBOX8)3–5, are key regulators of mouse ZGA. Mice deficient for maternally transcribed Obox1/2/5/7 and zygotically expressed Obox3/4 had a two-cell to four-cell arrest, accompanied by impaired ZGA. The Obox knockout defects could be rescued by restoring either maternal and zygotic OBOX, which suggests that maternal and zygotic OBOX redundantly support embryonic development. Chromatin-binding analysis showed that Obox knockout preferentially affected OBOX-binding targets. Mechanistically, OBOX facilitated the ‘preconfiguration’ of RNA polymerase II, as the polymerase relocated from the initial one-cell binding targets to ZGA gene promoters and distal enhancers. Impaired polymerase II preconfiguration in Obox mutants was accompanied by defective ZGA and chromatin accessibility transition, as well as aberrant activation of one-cell polymerase II targets. Finally, ectopic expression of OBOX activated ZGA genes and MERVL repeats in mouse embryonic stem cells. These data thus demonstrate that OBOX regulates mouse ZGA and early embryogenesis.

Date: 2023
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DOI: 10.1038/s41586-023-06428-3

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