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Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses (ATAC-seq)

ABSTRACT: Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses (ATAC-seq)

PROVIDER: PRJNA472897 | ENA |

REPOSITORIES: ENA

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Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Project description:Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-? exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.

| S-EPMC6082722 | biostudies-literature

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses (ATAC-seq)

Project description:Mesenchymal tumor subclones secrete cytokines that promote tumorigenesis and chemoresistance, but the mechanism that underlies this phenomenon remains poorly understood. Here we identify a de-repressed subclass of endogenous retroviruses (ERVs) that engage innate immune signaling in mesenchymal cancer cells. These Stimulated 3 Prime Antisense Retroviral Coding Sequences (SPARCS) are oriented inversely in 3’UTRs of certain interferon-inducible genes, generating dsRNA following IFN exposure. Sensing of this dsRNA by MAVS fuels activation of TBK1, IRF3, and STAT1 signaling. SPARCS induction in human tumors is tightly associated with B2M and MHC class 1 antigen expression, mesenchymal markers, and downregulation of chromatin modifying enzymes. Cell lines poised to induce high levels of SPARCS expression are associated with an AXL positive mesenchymal cell state. These data unveil a novel subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer.

2019-10-15 | GSE114864 | GEO

Hijacking of transcriptional condensates by endogenous retroviruses

Project description:Hijacking of transcriptional condensates by endogenous retroviruses

| PRJNA669013 | ENA

H3.3 deposition at endogenous retroviruses in embryonic stem cells

Project description:We report DAXX-dependent deposition of histone H3.3 at at endogenous retroviruses in embryonic stem cells.

2015-07-16 | GSE70966 | GEO

Endogenous retroviruses promote prion-like spreading of proteopathic seeds

Project description:Prion-like spreading of protein misfolding is characteristic for neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like spreading of proteopathic seeds. To identify changes in the proteome of donor cells that might contribute to protein aggregate spreading, we performed mass spectrometry analyses of total cell lysates and donor EV fractions using N2a cells expressing HA epitope-tagged Sup35 NM prion protein at early (P07) and late passages (P16) post cryopreservation. Among the proteins increased in donor cells and EVs upon prolonged culture, we identified mouse endogenous MLV retrovirus proteins to be highly increased.

2023-10-18 | PXD043201 | Pride

TRIM28 silences endogenous retroviruses in neural progenitor cells

Project description:Here we show that in neural progenitor cells (NPCs) TRIM28 silences transcription of two groups of endogenous retroviruses (ERVs): IAP1 and MMERVK10C. Derepression of ERVs in Trim28-deficient NPCs was associated with a loss of H3K9me3 and resulted in transcriptional upregulation and reverse transcription. These findings demonstrate a unique dynamic transcriptional regulation of ERVs in NPCs. Analysis of upregulation of ERVs in Trim28-deficient NPCs

2015-01-07 | E-GEOD-45930 | biostudies-arrayexpress

Regulatory evolution of innate immunity through co-option of endogenous retroviruses.

Project description:Endogenous retroviruses (ERVs) are abundant in mammalian genomes and contain sequences modulating transcription. The impact of ERV propagation on the evolution of gene regulation remains poorly understood. We found that ERVs have shaped the evolution of a transcriptional network underlying the interferon (IFN) response, a major branch of innate immunity, and that lineage-specific ERVs have dispersed numerous IFN-inducible enhancers independently in diverse mammalian genomes. CRISPR-Cas9 deletion of a subset of these ERV elements in the human genome impaired expression of adjacent IFN-induced genes and revealed their involvement in the regulation of essential immune functions, including activation of the AIM2 inflammasome. Although these regulatory sequences likely arose in ancient viruses, they now constitute a dynamic reservoir of IFN-inducible enhancers fueling genetic innovation in mammalian immune defenses.

| S-EPMC4887275 | biostudies-literature

TRIM28 silences endogenous retroviruses in neural progenitor cells

2015-01-07 | GSE45930 | GEO

Activation of endogenous retroviruses during brain development causes neuroinflammation

Project description:Activation of endogenous retroviruses during brain development causes neuroinflammation

| PRJNA645401 | ENA

Morc3 silences endogenous retroviruses in mouse embryonic stem cells

Project description:Morc3 silences endogenous retroviruses in mouse embryonic stem cells

| PRJNA727542 | ENA