Rotaviruses (RV), a leading cause of severe diarrhea in young children and livestock worldwide, have evolved multiple strategies to counteract the host innate immunity. Despite a worldwide administration, the current RV vaccines have limited efficacy (at most 50%) in low- and middle-income countries, underscoring an urgent need of developing more effective vaccine and antiviral program. Here, using a genome-wide CRISPR/Cas9 screen, RNA sequencing, and ChIP, we determined that ING3 functions as a novel ‘gatekeeper’ of ERV expression and IFN homeostasis. ING3 deficiency leads to ERV de-suppression, activation of the MDA5-MAVS signaling, and excessive IFN production.

We describe a new role for inhibitor of growth family member 3 (ING3), to add to an emerging group of ERV transcriptional regulators. Our results show that ING3 binds to several ERV promoters (for instance MER21C) and establishes an EZH2-mediated H3K27 trimethylation modification. Loss of ING3 leads to decreases of H3K27 trimethylation enrichment at ERVs, induction of MDA5-MAVSinterferon signaling, and functional inhibition of several virus infections. These data demonstrate an important new function of ING3 in ERV silencing and contributing to innate immune regulation in somatic cells.

Yanhua Song from Jiangsu Academy of Agricultural Sciences and Gaopeng Hou from the University of Washington are the co-first authors of this paper. The research was conducted by Yanhua Song during her postdoctoral fellowship, in collaboration with Professor Harry B Greenberg from Stanford University and Professor Siyuan Ding from The University of Washington.

The authors would like to thank Dr. Qin Yan (Yale University) and Drs. Michael Diamond, Jacco Boon, and Sebla Kutluay (Washington University in St. Louis) for constructive comments and suggestions.

Figure 1. ERVs activate MDA5-MAVS signaling in ING3 KO cells.

Figure 2. ING3 recruits EZH2 and H3K27 trimethylation to the ERV promoters.

Paper link：https://academic.oup.com/nar/article/49/22/12706/6430487