a, IHC staining of pRIP3. Data shown are related to those in Fig. 4b. n = 3 mice. b, TUNEL staining of ileum from mice of different genotypes (as indicated) at 8 dpi. Data shown are related to those in Fig. 4c. n = 3 mice. c, qPCR of Ifnb1 and Zbp1 expression in 4-dpi small-intestinal crypts and organoids. n = 3 experimental repeats. d, Immunoblot of ZBP1 from 4-dpi small-intestinal crypts. n = 2 mice. e, qPCR of expression of interferon-stimulated genes. n = 3 experimental repeats. f, qPCR of relative expression of interferon-stimulated genes in Setdb1 wild-type organoids treated as indicated. n = 2 experimental repeats. g, Representative images of PI-traced organoids. The procedure of the treatments with 0.1 ng ml−1 IFNB1, 10 μg ml−1 IFNAR and 200 nM 4-OHT is shown to the right of the top panel. The bottom panel to the right of the images shows the statistics of relative PI area per organoid (n = 10 organoids). The bottom panel on the far right shows ZBP1 expression level. n = 2 experimental repeats. h, Truncated and mutated ZBP1, as used in Fig. 4h. The expressions of full-length ZBP1 (ZBP1-FL) and ZBP1(RHIM) (ZRHIM) were confirmed by anti-ZBP1 antibody (sc-271483) raised against amino acids 1–300 of mouse ZBP1, whereas ZBP1(ΔZα) was confirmed by anti-Flag antibody. The asterisk marks a specific band of ΔZα. The experiment was repeated three times. i, Representative images of GFP+ spheroids. These images are related to the right histogram of Fig. 4h. The experiment was repeated three times. j, Dot blot by J2 antibody of dsRNA from 4-dpi intestinal crypts. n = 3 experimental repeats. k, J2 staining revealed dsRNA enrichment in SETDB1-deprived organoids. n = 2 experimental repeats. Scale bars, 5 μm. l, RNA-seq for repeats revealed the level of ERVs in different cells, including ISCs, B cells, immortalized myofibroblast (iMEFs), pro-B cells and mouse embryonic stem cell (mESCs). m, H3K9me3 intensity profiles on different ERVs in ISCs. Next-generation sequencing plots show the fold of enrichment of H3K9me3 from −5 kb to 5 kb around genomic ERV elements in ISCs. TSS, transcription start site of ERV. TES, transcription end site. n, Schematic of CLIP assay. Data are shown in Fig. 4j. o, PCR with reverse transcription was performed with RNAs in ZBP1 immunoprecipitated from Setdb1-null crypts. The PCR products using specific primers of six ERVs (Fig. 4i) were sequenced (bottom sequences) and aligned to Repbase (top sequences), RNA of 4-dpi crypts from Setdb1iIEC-KO mice. n = 2 mice. p, Biopsies from patients with IBD and unaffected controls (control, n = 5; Crohn’s disease (CD), n = 6; ulcerative colitis (UC), n = 4) show increased virus mimicry repeats in patients with IBD. Scale bars, 50 μm. Data are mean ± s.e.m. P values were determined by two-sided unpaired t-test. NS, not significant (P > 0.05). Source Data