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Transposon-triggered innate immune response confers cancer resistance to the blind mole rat

Abstract

Blind mole rats (BMRs) are small rodents, characterized by an exceptionally long lifespan (>21 years) and resistance to both spontaneous and induced tumorigenesis. Here we report that cancer resistance in the BMR is mediated by retrotransposable elements (RTEs). Cells and tissues of BMRs express very low levels of DNA methyltransferase 1. Following cell hyperplasia, the BMR genome DNA loses methylation, resulting in the activation of RTEs. Upregulated RTEs form cytoplasmic RNA–DNA hybrids, which activate the cGAS–STING pathway to induce cell death. Although this mechanism is enhanced in the BMR, we show that it functions in mice and humans. We propose that RTEs were co-opted to serve as tumor suppressors that monitor cell proliferation and are activated in premalignant cells to trigger cell death via activation of the innate immune response. Activation of RTEs is a double-edged sword, serving as a tumor suppressor but contributing to aging in late life via the induction of sterile inflammation.

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Fig. 1: Activation of the IFN response in overproliferating BMR cells triggers CCD.
Fig. 2: Retrotransposons are activated in overproliferating BMR cells to trigger IFN and CCD due to naturally weak DNMT1.
Fig. 3: Naturally weak DNMT1 in BMR is responsible for RTE induction and CCD.
Fig. 4: The cGAS–STING pathway is activated in overproliferating BMR cells by RNA–DNA hybrids and is required to induce the IFN response and CCD.
Fig. 5: Treatment with NRTIs or the knockdown of cGAS or STING enhances the malignant transformation of BMR cells.
Fig. 6: Transposons can act as tumor suppressors.
Fig. 7: Cancer cells with higher expression levels of TEs tend to carry more mutations in genes of the type I IFN pathway.

Data availability

Most data are included in the figures. The exact P values, if applicable, are included in the source data. RNA-seq and MeDIP data have been deposited in the Gene Expression Omnibus (GEO) under accession no. GSE181413. Normalized methylation values of the Illumina microarray (HorvathMammalMethylChip40) are available at the GEO under accession no. GSE181732. The RNA-seq data of 188 lung cancer cell lines were obtained from the Broad Institute (https://sites.broadinstitute.org/ccle/). The cell-line mutation information was obtained from http://amp.pharm.mssm.edu/Harmonizome/. Source data are provided with this paper.

Code availability

All codes used in the current study have been deposited at https://github.com/qwzhang0601/Transposon-triggered-innate-immune-response-confers-cancer-resistance-to-the-blind-mole-rat.

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Acknowledgements

This research was supported by grants from the US National Institutes of Health to Z. Zhang (grant no. AG047200), A.S. (grant no. AG047200) and V.G. (grant nos AG047200 and AG051449).

Author information

Authors and Affiliations

Authors

Contributions

Y.Z., M.S., S.H., E.N., A.S. and V.G. designed the research. Y.Z. performed most of the experiments. E.O. performed the experiments with DNMT1 expression. J.L. performed the DNA-damage experiments. Q.Z., J.Y.L., Z. Zheng and Z. Zhang analyzed data. Z.K. and J.A. performed the DMBA–TPA experiments. Q.L., A.G., Y.S.L., J.H., J.L. and Z. Zheng provided help with experiments. A.S. and V.G. supervised the research. Y.Z., A.S. and V.G. wrote the paper with input from all authors.

Corresponding authors

Correspondence to Andrei Seluanov or Vera Gorbunova.

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The authors declare no competing interests.

Additional information

Peer review information Nature Immunology thanks the anonymous reviewers for their contribution to the peer review of this work. Jamie D. K. Wilson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Activation of SASP in overproliferating BMR cells and differential gene expression in BMR and mice tissues.

(a) qRT-PCR showing senescence markers P21 and P16 were increased with proliferation of BMR cells. (b) SASP factors IL1b, IL6, IL8, and MMP12 were increased with proliferation of BMR cells. (c) KEGG pathway enrichment analysis of consistently upregulated and downregulated genes in the BMR tissues. RNA samples from 8 different tissues, including intestine, kidney, liver, lung, muscle, skin, spleen, and white adipose tissues (WAT) of BMR and mice were sequenced. A gene is defined as consistently upregulated gene if it expresses higher in BMR than in mice in at least six tissues. P values were adjusted by FDR. (d) A boxplot showing different fold changes of genes from IFN and NF-κB pathways comparing BMR and mice tissues. Center lines represent median, bounds of box are the 1st quartile and 3rd quartile, and whiskers are drawn down to the 10th percentile and up to the 90th percentile. (e) A heatmap showing differential gene expression in BMR CCD cells.

Source data

Extended Data Fig. 2 Transcriptional start sites of B1 and L1 in BMR CCD cells.

(a) Transcriptional start sites of B1 and L1 in CCD cells of BMR. 5′ RACE was performed using BMR fibroblasts undergoing CCD. The RACE product was ligated into T vector and colonies were sequenced. A multiple alignment of the products was generated against the consensus SINE B1 sequence or a predicted active L1 family homologous to mouse L1MdaI, respectively. The alignment was generated with Clustal Omega and displayed by Jalview. The location of gene-specific primer 2 (GSP2) for both B1 and L1 were shown under the consensus sequence. (b) Summary of the mapping data of L1 5′ RACE. The location of transcription start sites were shown relative to the consensus start site.

Extended Data Fig. 3 RNA expression of SINE B1, B2 and IFNB1 in carcinogen DMBA/TPA treated BMR and mouse skin.

BMR and mice were topically treated with DMBA followed by treatment of TPA 3 days after DMBA. Two weeks after treatment, biopsy was taken from treated area, and RNA was extracted. Expression of SINE B1, B2 and IFNB1 was determined by qRT-PCR. Data are mean ± SEM of 3 biological replicates of 2 technical repeats.

Source data

Extended Data Fig. 4 Naturally low levels of DNMT1 result in loss of DNA methylation and SASP in overproliferating BMR cells.

(a) Unsupervised hierarchical clustering of DNA samples from BMR and mouse fibroblasts with low and high PDs. The Average linkage hierarchical clustering is based on the inter-array correlation coefficient (Pearson correlation). The cluster branches (first color band) correspond to species (second color band, blue = BMR, cyan = mouse). Third color band: high PD (O; black) versus low PD (Y; white). (b) A heatmap showing differentially methylated elements determined using Methylated DNA immunoprecipitation (MeDIP). Differentially methylated regions (DMRs) were annotated against BMR genome. Totally 39 TE families were hyper-methylated and 60 TE families were hypo-methylated in dying BMR cells. Hypo-methylated TEs are enriched with B1 (especially PB1D9 family) and L1. (c) A heatmap showing generally lower expression levels of DNMT1 in 8 different tissues of BMR than mice. (d) alignment of partial sequence of human, mouse and BMR DNMT1 protein including immunogen recognized by the antibody used (Abcam ab13537). The immunogen is highly conserved across species, which is identical between human and BMR, and only 3 different amino acids different in mouse DNMT1. (e) Western blot detecting endogenous DNMT1 of primary and Large T transformed BMR cells. Large T is known to elevate DNMT1 expression. The significant band shows that the antibody is capable to detect BMR DNMT1. The experiment was repeated three times independently with similar results. (f) qRT-PCR showing overexpression of human DNMT1 in BMR cells. (g) Overexpression of DNMT1 restored global DNA methylation in BMR cells. (h) qRT-PCR showing repressed senescence factors by overexpression of DNMT1. Data are mean ± SD of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired two-sided Student’s t-test.

Source data

Extended Data Fig. 5 BMR cells undergo DNA damage induced by IFN.

(a) Images and quantification of comet assay detecting DNA damage of BMR cells with proliferation. Scale bar, 10 μM. (b) Images and quantification of immunofluorescence detecting γH2AX foci of BMR cells with proliferation. Scale bar, 5 μM. (c) DNA damage response of BMR cells with proliferation. Western blot was performed to show the phosphorylation of Chk2 (Thr68) and p53 (Ser15). The experiment was repeated three times independently with similar results. (d) Comet assay showing reduced DNA damage by overexpression of DNMT1. Scale bar, 10 μM. (e) Comet assay showing DNA damage induced by IFN. Young, growing BMR cells were treated with either medium containing BMR IFN or conditioned medium from old, dying BMR cells for 12 days before harvesting for comet assay. Scale bar, 10 μM. Tail DNA percentage (a, d, and e) or γH2AX (b) foci were quantified from 100 cells per group. Data are mean ± . **P < 0.01, ***P < 0.001 by unpaired two-sided Student’s t-test.

Source data

Extended Data Fig. 6 Nucleoside reverse-transcriptase inhibitors (NRTIs) treatment reduces RNA/DNA hybrids and represses cGAS–STING pathway.

(a) Images of cytoplasmic double-stranded (ds) RNA in young and dying BMR cells stained with J2 antibody. Cells treated with RNase III and with secondary antibody only lost the signals, confirming the specificity of J2 antibody recognizing dsRNA. Scale bar, 5 μM. The experiment was repeated three times independently with similar results. (b) Images of cytoplasmic RNA/DNA hybrids in BMR cells stained with S9.6 antibody. Treatment of RNase H, which specifically degrades RNA/DNA hybrids, and with secondary antibody only didn’t yield signals, confirming that S9.6 antibody specifically recognizes RNA/DNA hybrids. Scale bar, 5 μM. The experiment was repeated three times independently with similar results. (c) Reduced cytoplasmic RNA/DNA hybrids by NRTIs treatment stained by S9.6 antibody in BMR cells. Scale bar, 5 μM. Immunofluorescence intensities were quantified from 30 cells per group. (d) Comet assay showing reduced DNA damage by NRTIs treatment in BMR cells. Scale bar, 10 μM. Tail DNA percentages were quantified from 100 cells per group. (e-f) knockdown of cGAS (e) and STING (f) were determined by qRT-PCR and western blot. (g) growth curve showing that knockdown of dsRNA-sensing genes TLR3, MAVS, MDA-5, and IRG-1 didn’t rescue CCD. Data are mean ± SD of 3 independent experiments. **P < 0.01, ***P < 0.001 by unpaired two-sided Student’s t-test.

Source data

Extended Data Fig. 7 Roles of DNMT1 and RTEs in tumorigenesis in mice and human cells.

(a) Knockdown of DNMT1 in HeLa and HT1080 cancer cells as determined by Western blot. The experiment was repeated three times independently with similar results. (b-c) Knockdown of DNMT1 repressed proliferation of HT1080 cells in vitro. Clonogenic assay was performed with crystal violet staining and colonies areas were quantified (c). N = 3 technical replicates. Experiment was repeated three times independently with similar results. (d) Growth curve of DMBA/TPA-induced papilloma in mice treated with or without abacavir. Abacavir treated alone repressed DMBA/TPA induced papilloma. Experiment was performed using eight animals for each group. (e) Images of SKH1 hairless mice with papilloma induced by DMBA/TPA. 5-Aza repressed formation of papilloma, while abacavir restored this repression. (f) qRT-PCR showing overexpression of SINE B1 in HeLa cells. N = 3 technical replicates. (g) Western blot showing overexpression of L1 (ORFeus) in HeLa cells by detecting ORF1p. The experiment was repeated three times independently with similar results. (h) qRT-PCR showing activation of IFNB1 in HeLa cells by overexpression of SINE B1 and L1 (ORFeus). N = 3 technical replicates. Data are mean ± SD (c, f, and h) or mean ± SEM (d). * P < 0.05, **P < 0.01, ***P < 0.001 by unpaired two-sided Student’s t-test.

Source data

Supplementary information

Reporting Summary

Supplementary Data 1

IFN-pathway gene list.

Supplementary Data 2

CCLE accession number and web links.

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Zhao, Y., Oreskovic, E., Zhang, Q. et al. Transposon-triggered innate immune response confers cancer resistance to the blind mole rat. Nat Immunol 22, 1219–1230 (2021). https://doi.org/10.1038/s41590-021-01027-8

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