Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Griffin, Gabriel K.; Wu, Jingyi; Iracheta-Vellve, Arvin; Patti, James C.; Hsu, Jeffrey; Davis, Thomas; Dele-Oni, Deborah; Du, Peter; Halawi, Aya; Ishizuka, Jeffrey J.; Kim, Sarah Y; Klaeger, Susan; Knudsen, Nelson H.; Miller, Brian C.; Nguyen, Tung H.; Olander, Kira E.; Papanastasiou, Malvina; Rachimi, Suzanna; Robitschek, Emily; Schneider, Emily M.; Yeary, Mitchell D.; Zimmer, Margaret D.; Jaffe, Jacob D.; Carr, Steven A.; Doench, John G.; Haining, W. Nicholas; Yates, Kathleen B.; Manguso, Robert T.; Bernstein, B

doi:10.1038/s41586-021-03520-4

Cited by 242 publications

(223 citation statements)

References 58 publications

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“…In multicellular eukaryotes, heterochromatin serves two main functions: it silences the transcription of satellite repeats and transposons 3 and it silences tissue-specific genes during development 4 , 5 . Consistent with this, the loss of appropriately targeted heterochromatin is associated with a loss of tissue integrity, ageing and cancer 4 – 8 .…”

Section: Mainsupporting

confidence: 52%

H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

et al. 2021

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The developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity.

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Section: Mainsupporting

confidence: 52%

H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

et al. 2021

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“…Recent studies have found numerous peptides derived from translation outside of canonical coding regions in tumor cells, and, presumably, some of these events may be specific to the in vivo context. Additionally, the system reported here will complement the study of post-translationally modified peptides 47 , transposable element-derived peptides 48 , and bacterially-derived peptides 49 as many of these events will be influenced physiological cues from the in vivo microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the tumor-specific immunopeptidome in vivo with genetically engineered mouse models

Stopfer

Sanders

et al. 2021

Preprint

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Effective immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex Class I (MHC-I). Recent developments in proteomics have improved the identification of peptides that are naturally presented by MHC-I, collectively known as the “immunopeptidome”. Current approaches to profile tumor immunopeptidomes have been limited to in vitro investigation, which fails to capture the in vivo repertoire of MHC-I peptides, or bulk tumor lysates, which are obscured by the lack of tumor-specific MHC-I isolation. To overcome these limitations, we report here the engineering of a Cre recombinase-inducible affinity tag into the endogenous mouse MHC-I gene and targeting of this allele to the KrasLSL-G12D/+; p53fl/fl (KP) mouse model (KP; KbStrep). This novel approach has allowed us to isolate tumor-specific MHC-I peptides from autochthonous pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) in vivo. With this powerful analytical tool, we were able to profile the evolution of the LUAD immunopeptidome through tumor progression and show that in vivo MHC-I presentation is shaped by post-translational mechanisms. We also uncovered novel, putative LUAD tumor associated antigens (TAAs). Many peptides that were recurrently presented in vivo exhibited very low expression of the cognate mRNA, provoking reconsideration of antigen prediction pipelines that triage peptides according to transcript abundance. Beyond cancer, the KbStrep allele is compatible with a broad range of Cre-driver lines to explore antigen presentation in vivo in the pursuit of understanding basic immunology, infectious disease, and autoimmunity.

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“…Thus, one may hypothesize these circulating neo-lncRNAs could also be translated in the host cells and act as a decoy to the immune system. An attractive scenario is that some tumoral cells not only could silence their own HLA system using epigenetic regulation as recently shown 53 , as some sort of invisibility blanket, but would transfer information and tumor specific neoantigens lncRNA templates to non-tumoral adjacent cells. With their fully operational antigen presenting machinery, these cells would then divert the anti-tumoral immune response away from the true tumor.…”

Section: Discussionmentioning

confidence: 99%

Prostate cancer urinary Extracellular Vesicles are enriched in cytoplasmic intron-free mRNAs and circular/long noncoding RNAs with functional significance

Almeida¹,

Gabriel²,

Firlej³

et al. 2021

Preprint

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Long noncoding (lnc)RNAs modulate gene expression alongside presenting unexpected source of neoantigens. Despite their immense interest, their ability to be transferred and control adjacent cells is unknown. Extracellular Vesicles (EVs) offer a protective environment for nucleic acids, with pro and anti-tumorigenic functions by controlling the immune response. In contrast to extracellular non-vesicular RNA, few studies have addressed the full RNA content within human fluids’ EVs and none have compared them with their tissue of origin. Here, we performed Total RNA-Sequencing on 6 Formaldehyde-Fixed-Parafilm-Embedded (FFPE) prostate cancer (PCa) tumor tissues and their paired urinary (u)EVs to provide the first whole transcriptome comparison from the same patients. UEVs contain simplified transcriptome with intron-free cytoplasmic transcripts and specific lnc/circular (circ)RNAs, strikingly common to all patients. Our full cellular and EVs transcriptome comparison within 3 common PCa cell lines identified a set of overlapping 14 uEV-circRNAs characterized as essential for prostate cell proliferation in vitro and 15 uEV-lncRNAs that we predicted to encode 768 high-affinity neoantigens. Our dual analysis of EVs-lnc/circRNAs both in urines’ and in vitro’s EVs provides a fundamental resource for future uEV-lnc/circRNAs phenotypic characterization involved in PCa.

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Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Cited by 242 publications

References 58 publications

H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

Deciphering the tumor-specific immunopeptidome in vivo with genetically engineered mouse models

Prostate cancer urinary Extracellular Vesicles are enriched in cytoplasmic intron-free mRNAs and circular/long noncoding RNAs with functional significance

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