Scientists from China discovered new regulator of endogenous retroviruses in totipotent cells

Scientists at Nankai Univesity, China, in collaboration with their counterparts from Singapore, have discovered a protein mediator Zscan4c plays a critical role in early mouse embryo development. This finding was reported on 15th July 2019 in the advanced online issue of the science journal Nucleic Acids Research.

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Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that are derived from retroviruses. Ancient retroviral infections have occasionally resulted in such integrations into the germline of the host, becoming endogenous retroviruses. Most ERV copies have accumulated mutations over evolutionary time and lost the capability of infection to other cells. ERVs had been deemed as junk DNA in genome which didn’t have any functionality. However, this study show that ERVs, expressed in totipotent 2-cell/4-cell embryos, are activated by Zscan4c and function as enhancers in ESCs and totipotent cells.

Recently Xinyi Lu’s team from Nankai University in China investigated the ERV expression pattern in early embryo. First, they explored the expression feature of ERVs in mouse embryos and found that ERV MERVL and transcription factor Zscan4 are expressed in totipotent 2-cell and 4-cell embryos at high level.

“ERVs are activated during embryo development is counter-intuitive considering that ERVs are supposed to influence the genetic stability,” Principal investigator Xinyi Lu said, then he added, “It is important to decipher the regulation mechanism of ERVs expression.”

The team examined the possibility for Zscan4c as an activator of MT2/MERVL by depleting and overexpressing Zscan4c. It turned out that Zscan4c can upregulate the expression of MERVL and totipotency-associated 2-cell/4-cell genes. Then, they found that MERVL-LTR nearby genes significantly overlapped with upregulated genes after Zscan4c overexpression. Among overlapped genes, most of them were expressed prior to the 4-cell stage, implying that Zscan4c may activate 2-cell/4-cell embryo genes through the possible enhancer role of MERVL. Afterwards, they confirmed that MERVL-LTR is enhancer that activate nearby genes. Furthermore, MT2 activation is accompanied by open chromatin deposition and recruitment of GBAF chromatin remodeling complex through SCAN domain.

This study highlights the important role of junk DNA MERVL-LTR as functional enhancer element to activate genes in embryo development by the help of Zscan4.

Weiyu Zhang, Fuquan Chen, Ruiqing Chen, Dan Xie, Jiao Yang, Xin Zhao, Renpeng Guo, Yongwang Zhang, Yang Shen, Jonathan Göke, Lin Liu and Xinyi Lu. Zscan4c activates endogenous retrovirus MERVL and cleavage embryo genes. Nucleic Acids Research, 2019. https://doi.org/10.1093/nar/gkz594


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