On 8th March, the respective research groups of Prof. Yang Peng and Prof. Wang Yixuan from the School of Life Science and Technology of Tongji University jointly published a paper entitled Species-specific KRAB-ZFPs function as repressors of retroviruses by targeting PBS regions in Proceedings of the National Academy of Sciences (PNAS).  

The research reports that the zinc finger protein ZFP961 from mice and the zinc finger protein ZNF417/ZNF587 from humans both recruit KAP1, SETDB1 and other epi-repressors in ERVs by targeting PBS-Lys, and promote the establishment of H3K9me3 modification in heterochromatin. In addition, these zinc finger proteins can help host cells resist infection by exogenous retroviruses (such as HIV-1) containing PBS-Lys elements, inhibiting their transcription and integration processes.

The paper jointly published in the Proceedings of the National Academy of Sciences

Over millions of years, retroviruses, during their invasion of host eukaryotes, gradually integrated into the genome of host cells, becoming endogenous retroviruses (ERVs). These ERVs comprise approximately 8% of the human genome and retain many functional retroviral elements, including the tRNA primer binding site sequence (PBS), originally used to initiate reverse transcription. They play an important role in embryonic genome activation, such as high expression of ERVK containing PBS-Lys elements in early human embryos at the 8-cell stage with totipotency. Although most ERVs have lost their ability to replicate themselves in evolution, they still retain the ability to activate transcriptional regulation of surrounding genes, thus threatening the stability of the genome. In mammals, one of the host’s strategies to suppress ERVs is to use KRAB domain-containing zinc finger proteins (KRAB-ZFPs) to establish heterochromatin modifications in the ERV region in order to inhibit their transcriptional activity.

This research not only identified zinc finger proteins that recognize and inhibit PBS-Lys elements in mice and humans, but also screened a variety of zinc finger proteins that target other types of PBS. These complement many studies carried out on binding inhibition between zinc finger proteins and ERVs. In addition, the study also utilizes the conservation of PBS sequences to propose that zinc finger proteins can inhibit the transcription and integration of exogenous viruses by targeting PBS sites, thus explaining the mechanism by which host cells use zinc finger proteins to resist exogenous retrovirus infection.

Yang Bo, a doctoral student at the School of Life Science and Technology of Tongji University, is the first author of the paper, while Prof. Yang Peng and Prof. Wang Yixuan are the co-corresponding authors. The thesis was also supported and helped by Professor Chen Zhenxia of Huazhong Agricultural University. The research was supported by the Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the Shanghai Dawning Program and the Qixing Program.