Gut stem cell necroptosis by genome instability triggers bowel inflammation

Abstract

The aetiology of inflammatory bowel disease (IBD) is a multifactorial interplay between heredity and environment1,2. Here we report that deficiency in SETDB1, a histone methyltransferase that mediates the trimethylation of histone H3 at lysine 9, participates in the pathogenesis of IBD. We found that levels of SETDB1 are decreased in patients with IBD, and that mice with reduced SETDB1 in intestinal stem cells developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability3, and the loss of SETDB1 in intestinal stem cells released repression of endogenous retroviruses (retrovirus-like elements with long repeats that, in humans, comprise approximately 8% of the genome). Excessive viral mimicry generated by motivated endogenous retroviruses triggered Z-DNA-binding protein 1 (ZBP1)-dependent necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted bowel inflammation. Genome instability, reactive endogenous retroviruses, upregulation of ZBP1 and necroptosis were all seen in patients with IBD. Pharmaceutical inhibition of RIP3 showed a curative effect in SETDB1-deficient mice, which suggests that targeting necroptosis of intestinal stem cells may represent an approach for the treatment of severe IBD.

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Fig. 1: Epithelial SETDB1 depression triggers IBD.
Fig. 2: Bowel inflammation is associated with genome instability and stem cell death.
Fig. 3: Necroptosis in SETDB1-deficient crypts links cell death to inflammation.
Fig. 4: ZBP1 senses ERV RNA and recruits RIP3 for necroptosis upon genome instability by SETDB1 deficiency.

Data availability

The datasets generated during the current study are available in the GEO database, with the accession code GSE129174. All other data generated in this Article are provided in the Supplementary Information and Source Data; Source Data for Figs. 14 and Extended Data Figs. 19 are provided with the paper. The Setdb1fl/fl mice are available from the corresponding authors upon request.

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Acknowledgements

We thank L. Hui, Y. Chen, J. Qin and Y. Nie for experimental resources, and L. Yao for technical support. The study was supported by the National Natural Science Foundation of China (81788101 to J. Han, 81472725 to W.M., 31971329 and 31501096 to M.L., and 81602675 to J. Hu), the Fundamental Research Funds for the Central Universities (20720160072 and 20720190086 to W.M.).

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Authors

Contributions

R.W., H.L., J. Han and W.M. designed experiments, performed data analyses and wrote the manuscript. R.W., H.L., Y.L., H.N., Z.-Y.C., Z.-H.Y. and W.L. performed experiments. B.L., H.C., X.Q. and P.L. provided specimens from patient with IBD. J.W. provided relevant mice. R.W., H.L., Z.-Y.C., J. Hu, Y.L. and M.L. performed biochemical analysis of Setdb1-deficient mice. W.M. supervised the study.

Corresponding authors

Correspondence to Jiahuai Han or Wei Mo.

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The authors declare no competing interests.

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Peer review information Nature thanks Alexander N. Poltorak and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Mouse model to mimic SETDB1 inactivation in patients with IBD.

a, SETDB1 IHC of human surgical samples; data are related those in Fig. 1d. Insets show high magnifications of crypts. The complete set of images is included in Supplementary Fig. 2 (n = 17). n = 30 samples from patients with IBD. b, Mouse model and work flow. One dose of tamoxifen was used. c, Left, SETDB1 IHC in mouse ileal and colonic sections. SETDB1 is highly expressed in ISCs (inset in top panel; red arrows) and is absent in the Paneth cell (inset in top panel, black arrow). Middle and right, SETDB1 disappears in epithelial cells (dotted line and insets) and remains in non-epithelial cells. At least three sections were taken each day with similar results. d, Body weight curves of Setdb1fl/fl and Setdb1iIEC-KO mice after tamoxifen induction (n = 20 mice). P values and significance were determined by a two-sided unpaired t-test, ***P < 0.001. e, Anatomy images of 8-dpi intestine of Setdb1fl/fl and Setdb1iIEC-KO mice after tamoxifen induction. Red arrow shows signs of watery diarrhoea; n = 3 mice were repeated. f, Kaplan–Meier survival curves of Setdb1fl/fl and Setdb1iIEC-KO mice after tamoxifen induction (n = 20 mice), P values were determined by log–rank test, 95% confidence interval of ratio. Scale bars, 50 μm. Data are mean ± s.e.m. Source Data

Extended Data Fig. 2 Dysplasia and inflammation occur after Setdb1 deletion in the mouse intestine.

a, Ki67 staining of ileum and colon of mice at 8 dpi (n = 6 mice). b, Lysozyme (Paneth cells) and MUC2 (goblet cells) of ileum of mouse at 8 dpi (n = 6 mice). c, H & E staining revealed a considerable breakdown of the colonic epithelium barrier at 10 dpi in mice of the indicated genotypes. Insets are magnified crypts, showing crypt destruction and colitis (n = 3 mice). d, H & E images of VIL–CreERT2 mice induced with or without tamoxifen, n = 3 mice were repeated with no difference between two groups. e, Heat map of chemokines and interleukins in ileal and colonic lamina propria of 4-dpi and 8-dpi mice (n = 3 mice). Scale bars, 50 μm. Data are mean ± s.e.m. Source Data

Extended Data Fig. 3 VIL–Cre Setdb1fl/fl mice and mice with Setdb1 deleted specifically in ISCs also show inflammatory symptoms.

a, Weight (n = 10 mice of each genotype) and Kaplan–Meier survival curves (n = 12 mice of each genotype) of Setdb1fl/fl and VIL–Cre Setdb1fl/fl mice. The weight curve was determined by two-tailed t-test. P value of survival curve was determined by log–rank test, 95% confidence interval of ratio. b, Representative images of SETDB1-knockout efficacy of VIL–Cre Setdb1fl/fl mice (full knockout (KO), n = 6 mice; mosaic knockout, n = 2 mice were found). Dotted lines in the left panel denote that no SETDB1 expressed. Dotted lines in the right panel demonstrate that most of the cells expressed SETDB1; adenomas shown in c share a similar SETDB1 expression pattern, as they came from the same paraffin block. c, H & E staining of Setdb1 mosaic-knockout mice (postnatal day (P)42) developed aberrant crypts (top inset) and adenomas (bottom inset). n = 2 mice. d, H & E staining of Setdb1 full-knockout mice at P12 (n = 6 mice). Insets show the thin bowel and narrowed lumen of Setdb1 full-knockout mice. Dotted lines depict crypts. e, Staining for Ki67 (proliferative cells), lysozyme (Paneth cells) and MUC2 (goblet cells) from P12 ileal sections, as indicated. n = 50 crypt–villus axes. At least three individual experiments were performed and cells were counted, with similar results. f, Lymphocyte IHC signals in ileum or colon. n = 50 crypt–villus axes. Three individual experiments were performed with similar results. Box plots show median and 25th to 75th percentiles, and whiskers indicate the minimum and maximum values. g, Inflammatory bowel damage in Olfm4-creERT2;Setdb1fl/fl mice. H & E staining at 0 dpi and 8 dpi was compared (20 crypts or villi were counted). Scale bars, 50 μm. Data are mean ± s.e.m. Box plots show median and 25th to 75th percentiles, and whiskers indicate the minimum and maximum values. P values and significance were determined by two-sided unpaired t-test. NS, not significant; ***P < 0.001. Source Data

Extended Data Fig. 4 SETDB1 deficiency activates innate immunity and ISC death.

a, Schematic of RNA-seq. b, Heat map depiction of innate-immunity-related genes. c, Volcano plot of differentially expressed genes (log2-transformed fold change ≥ 3.5 or ≤ −3.5; P value < 0.001) at 2, 3 and 4 dpi. n = 1 mouse for each day. Details of statistical analysis are provided in Methods. d, Scenario of CLU+ revival stem cells (revSCs) for ISC injury. Revival stem cells are very rare under homoeostasis, but expanded rapidly upon injury of LGR5+ ISCs to regenerate the intestine. e, Representative images show GFP+ cells after tamoxifen induction in Lgr5-eGFP- Setdb1iIEC-KO mice. f, PI-traced organoids from VIL–CreERT2 Setdb1fl/fl mice treated with EtOH as control or 4-OHT to induce Setdb1 deletion (four individual experiments were performed with similar results). Panel to the right of the images is a statistical analysis of the relative PI area per organoid (n = 10 organoids). g, Images of single ISC-derived spheroids in WENR medium. Experiment was repeated three times, with similar results. h, Representative images of lower SETDB1 IHC intensity correlating with higher γH2AX IHC intensity. The complete set of images of γH2AX and SETDB1 IHC is provided in Supplementary Fig. 2. n = 23 samples. i, Representative images of γH2AX and TUNEL staining, n = 3 experimental repeats for each day. Scale bars, 50 μm. Data are mean ± s.e.m. P values were determined by two-sided unpaired t-test. Source Data

Extended Data Fig. 5 Apoptosis blockade does not rescue cell death by Setdb1 deletion in vivo and ex vivo.

a, H & E staining of ileum and colon from mice of different genotypes (as indicated) at 5 dpi. n = 3 mice. b, Microscopy image of PI-stained organoids. The panel to the right of the images is a statistical analysis of the relative PI area per organoid (n = 10 organoids). c, IHC staining of pRIP3 and pMLKL of ileal crypts (at 6 dpi) from continuous paraffin sections. n = 3 mice. d, Representative images of TUNEL signals in crypts. Experiment was performed on n = 3 mice individually, with similar results. Scale bars, 50 μm (a, b, d), 25 μm (c). Data are mean ± s.e.m. Significance was determined by two-sided unpaired t-test. NS, not significant; ***P < 0.001. Source Data

Extended Data Fig. 6 RIP1-kinase-independent necroptosis contributes to cell death in Setdb1-null organoids.

a, qPCR with reverse transcription of Tnf (n = 3 experimental repeats). b, Organoids from VIL–CreERT2 Setdb1fl/fl mice were treated with TNF neutralizing antibody, Nec-1 (RIP1-kinase inhibitor) or GSK'872 (RIP3-kinase inhibitor) with or without 4-OHT, as indicated. The panel to the right of the images is a statistical analysis of the relative PI area per organoid (n = 10 organoids). Three individual experiments were performed, with similar results. Scale bars, 50 μm. Data are mean ± s.e.m. P values were determined by two-sided unpaired t-test. NS, not significant; ***P < 0.001. Source Data

Extended Data Fig. 7 ZBP1 can be induced by IFN but the initiation of necroptosis by ZBP1 requires ERVs.

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

Extended Data Fig. 8 Bowel inflammation in Setdb1iIEC-Het mice.

a, Left, western blot of SETDB1 in 4-dpi crypts. Right, Quantification of western blot intensities (n = 4 mice). b, qPCR of relative expression of ERVs at 4 dpi, n = 7 mice. c, Representative immunofluorescence of γH2AX staining in 4-dpi ileal sections. n = 50 crypts. Experiments were repeated in three mice. d, TUNEL assay of 4-dpi ileal sections. n = 3 mice were examined. n = 50 crypts. e, The expression of genes related to the type-I-interferon pathway in 4-dpi crypts. n = 7 mice. f, The expression of chemokines and interleukins in 4-dpi crypts. n = 7 mice. g, H & E staining of 4-dpi intestinal sections, showing destroyed epithelium in Setdb1iIEC-Het mice. n = 2 mice were found within 13 mice collected. h, PI-traced organoids were counted, out of n = 10 organoids were examined in total. 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

Extended Data Fig. 9 Necroptosis is the primary cause of death in Setdb1iIEC-KO mice.

a, H & E staining of intestine sections at 8 dpi, from Setdb1fl/fl and Setdb1iIEC-KO mice treated with or without broad spectrum antibiotics (ABX) as indicated. n = 3 mice were collected and checked, with similar results. b, Kaplan–Meier survival curves of mice used in this study. c, H & E staining of intestine sections at 8 dpi from Setdb1fl/fl and Setdb1iIEC-KO mice treated with mock or GSK'872 as indicated. n = 3 mice were checked, with similar results. Scale bars, 50 μm. P values were determined by log–rank test, 95% confidence interval of ratio. NS, not significant (P > 0.05). Source Data

Extended Data Fig. 10 SETDB1 safeguards genome stability against ZBP1-mediated necroptosis in ISCs.

SETDB1 protects genome integrity by enforcing repression of ERVs. Once SETDB1 is dysfunctional, reactive ERVs can produce multiple viral mimicry dsRNAs to activate ZBP1 for RIP3–MLKL necroptosis. Pro-inflammatory necroptosis breaks the epithelial barrier and promotes bowel inflammation.

Extended Data Table 1 The most-significantly upregulated genes in mutant crypts

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Wang, R., Li, H., Wu, J. et al. Gut stem cell necroptosis by genome instability triggers bowel inflammation. Nature 580, 386–390 (2020). https://doi.org/10.1038/s41586-020-2127-x

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