Summary: Researchers have discovered how a fertilized egg cell, or zygote, activates its own genome—a process known as zygotic genome activation (ZGA). Their findings identify the OBOX family of genes as master regulators that help launch the embryo’s genetic program.
The study shows that OBOX genes direct the enzyme RNA polymerase II to transcribe the appropriate genes at the correct time, initiating the cascade of gene expression required for embryonic development. The researchers also report that multiple OBOX genes act redundantly, a likely evolutionary safeguard to ensure this essential developmental transition succeeds.
Key facts:
- The OBOX family is identified as crucial for awakening the genome of a newly fertilized egg (zygote).
- OBOX proteins guide RNA polymerase II to begin transcription of the genes that drive early embryo development.
- Functional redundancy among OBOX genes probably evolved to protect the vital maternal-to-zygotic transition.
Source: UC Davis
New collaborative research from teams in the United States and China reveals how a zygote “resets” so the embryo can follow its own genetic program.
Published July 17 in Nature, the study addresses a long-standing question in developmental biology: what initiates zygotic genome activation? Richard Schultz, research professor at the University of California, Davis School of Veterinary Medicine and a corresponding author on the paper, explains that a newly fertilized egg initially carries an inactive genome that must be awakened for embryogenesis to proceed.
“For the embryo to develop, the oocyte or egg must lose its previous identity and begin producing new components,” Schultz said. “Our results reveal the initial mechanisms that drive this transition.”
Zygotic genome activation requires the embryo to transcribe its DNA into messenger RNA (mRNA), which is then translated into proteins. The earliest genes transcribed act as master regulators that trigger subsequent gene networks, setting the embryo on a path toward forming all tissues. Until now, the identity of those first transcriptional activators in mammals remained unclear.
RNA polymerase II (Pol II) carries out transcription, but it requires direction from transcription factors to select the correct gene targets at the right times. Schultz and colleagues hypothesized that the necessary transcription factors would be supplied by dormant maternal mRNAs stored in the egg. Unlike somatic cells, oocytes accumulate mRNAs that remain translationally silent until maturation, when they are translated into proteins that drive early development.
OBOX1–8 identified as candidates
Working with Paula Stein and collaborators, Schultz’s group identified a family of PRD-like homeobox genes called OBOX, comprising eight members (OBOX1–8), as prime candidates. Expression patterns during early development pointed particularly to OBOX1, 2, 3, 4, 5 and 7. To test their roles, the team partnered with Wei Xie at Tsinghua University, Beijing.
Using mouse models, the researchers deleted multiple OBOX genes and then reintroduced them one by one to determine which were essential for ZGA. Embryos lacking the key OBOX genes arrested at the two- to four-cell stage, demonstrating a failure to properly activate the zygotic genome.
A striking and unanticipated finding was the high degree of redundancy among OBOX genes: the loss of a single family member could often be compensated by others. The authors suggest this redundancy reflects strong evolutionary pressure to safeguard the maternal-to-zygotic transition. Mechanistically, OBOX proteins promote proper Pol II “pre-configuration,” allowing Pol II to relocate from one-cell binding sites to promoters and distal enhancers of ZGA genes.
In mice, major genome activation occurs at the two-cell stage; in humans, it happens later—around the eight-cell stage. Whether a similar OBOX-dependent mechanism operates in human embryos remains an open question. The study also has implications for stem cell biology and our understanding of how cells are reprogrammed to a pluripotent state capable of producing any tissue.
The research team included Shuyan Ji, Fengling Chen, Jiacheng Wang, Ziming Zhou, Lijuan Wang, Qing Zhao, Zili Lin, Bofeng Liu, Kai Xu, Fangnong Lai, Zhuqing Xiong, Xiaoyu Hu, Tianxiang Kong, Feng Kong, Qiujun Wang, Qianhua Xu, Qiang Fan and Ling Liu from Tsinghua-Peking Center for Life Sciences and Tsinghua University; Carmen Williams from the National Institute of Environmental Health Sciences; and Bo Huang from Zhejiang University School of Medicine, among others.
Funding: This work was supported in part by grants from the National Natural Science Foundation of China, the National Key R&D Program of China, and the NIH.
About this genetics research news
Author: Andrew Fell
Source: UC Davis
Contact: Andrew Fell – UC Davis
Image: The image is credited to Neuroscience News
Original research: Closed access. “OBOX regulates murine zygotic genome activation and early development” by Richard Schultz et al., published in Nature.
Abstract
OBOX regulates murine zygotic genome activation and early development
Zygotic genome activation (ZGA) awakens the previously quiescent genome to enable the maternal-to-zygotic transition, but the in vivo identity of the transcription factors that drive mammalian ZGA has been unclear. This study demonstrates that the OBOX family (OBOX1–8), a group of PRD-like homeobox transcription factors, are key regulators of mouse ZGA. Mice lacking maternally expressed Obox1/2/5/7 combined with loss of zygotic Obox3/4 show arrest at the two- to four-cell stage and impaired ZGA. Maternal and zygotic OBOX act redundantly, since restoring either maternal or zygotic expression can rescue Obox knockout defects. Chromatin binding analyses indicate Obox knockout preferentially disrupts OBOX-bound targets. Mechanistically, OBOX promotes RNA Pol II pre-configuration, enabling Pol II to move from one-cell binding sites to promoters and distal enhancers of ZGA genes. Obox mutants display defective Pol II pre-configuration, impaired chromatin accessibility transitions, abnormal activation of one-cell Pol II targets, and compromised ZGA. Finally, ectopic OBOX expression in mouse embryonic stem cells activates ZGA genes and MERVL repeats, supporting the conclusion that OBOX controls murine ZGA and early embryogenesis.