Epigenetic therapy induces transcription of Inverted SINEs and ADAR1 dependency
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145639 | GEO | 2020/10/20
REPOSITORIES: GEO
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Project description:Loss of function mutations in SMARCB1 are prevalent in pediatric atypical teratoid rhabdoid tumors (ATRTs) and confer an oncogenic dependency on EZH2, providing a compelling rationale for treating these genetically defined cancers via EZH2 inhibition (EZH2i). EZH2i results in tumor regression in SMARCB1-deficient tumors in preclinical studies, but the molecular mechanism has not been fully elucidated. Here we found that the sensitivity of SMARCB1-deficient tumors to EZH2i is associated with the viral mimicry response that depends on both double-stranded RNA (dsRNA) and cytoplasmic DNA sensing pathways. Unlike other epigenetic therapies targeting transcriptional repressors, viral mimicry by EZH2i in SMARCB1-deficient tumors is not triggered by crypt initiation of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, we found that interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a positive feedback loop whereby interferon response leads to dsRNA formation from intronic ISGs and activation of viral mimicry. Moreover, EZH2i in ATRT cells also enhances the expression of full-length LINE-1 elements, leading to genomic instability and cGAS/STING response in a process dependent on reverse transcriptase activity. Supporting this mechanism, co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.
2024-09-05 | GSE213249 | GEO
Project description:Loss of function mutations in SMARCB1 are prevalent in pediatric atypical teratoid rhabdoid tumors (ATRTs) and confer an oncogenic dependency on EZH2, providing a compelling rationale for treating these genetically defined cancers via EZH2 inhibition (EZH2i). EZH2i results in tumor regression in SMARCB1-deficient tumors in preclinical studies, but the molecular mechanism has not been fully elucidated. Here we found that the sensitivity of SMARCB1-deficient tumors to EZH2i is associated with the viral mimicry response that depends on both double-stranded RNA (dsRNA) and cytoplasmic DNA sensing pathways. Unlike other epigenetic therapies targeting transcriptional repressors, viral mimicry by EZH2i in SMARCB1-deficient tumors is not triggered by crypt initiation of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, we found that interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a positive feedback loop whereby interferon response leads to dsRNA formation from intronic ISGs and activation of viral mimicry. Moreover, EZH2i in ATRT cells also enhances the expression of full-length LINE-1 elements, leading to genomic instability and cGAS/STING response in a process dependent on reverse transcriptase activity. Supporting this mechanism, co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.
2024-09-05 | GSE213248 | GEO
Project description:Epigenetic therapy induces transcription of Inverted SINEs and ADAR1 dependency
| PRJNA607783 | ENA
Project description:Adenosine deaminase acting on RNA 1 (ADAR1), is an enzyme that catalyzes the conversion of adenosine to inosine in double-stranded RNA, a process critical for regulation of innate immune response and distinguishing between ‘self and non-self RNA’. It is expressed as two isoforms: nucleolar p110 and cytoplasmic, interferon (IFN)-inducible, p150. The interactome of the p110 under steady-state conditions is well-studied; however, less is known about the interactions of the p150 isoform, particularly during IFN response. To elucidate ADAR1's protein interactions during IFN stimulation, alongside steady-state conditions, three distinct methods of enrichment were used followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). These included: immunoprecipitation (IP) of endogenous ADAR1, IP of Strep II-tagged ADAR1, and proximity labeling using BioID. Individual ADAR1 isoforms (p110 and p150) and their respective dsRNA binding-deficient mutants were created to discern isoform-specific and dsRNA-dependent interactions. Altogether, our results reveal a comprehensive ADAR1 interaction map, identifying both known and novel partners, and highlighting the isoform-specific and dsRNA-binding-dependent nature of ADAR1 interactions. Under IFN stimulation, ADAR1's interaction spectrum encompasses viral replication inhibitors and LINE-1 regulators. Mimicking viral infection with HMW poly(I:C) changed the proximal network of proteins for both isoforms. Our findings provide new insights into ADAR1's roles and its dynamic during IFN response.
2024-12-05 | PXD049689 | Pride
Project description:Adenosine deaminase acting on RNA 1 (ADAR1), is an enzyme that catalyzes the conversion of adenosine to inosine in double-stranded RNA, a process critical for regulation of innate immune response and distinguishing between ‘self and non-self RNA’. It is expressed as two isoforms: nucleolar p110 and cytoplasmic, interferon (IFN)-inducible, p150. The interactome of the p110 under steady-state conditions is well-studied; however, less is known about the interactions of the p150 isoform, particularly during IFN response. To elucidate ADAR1's protein interactions during IFN stimulation, alongside steady-state conditions, three distinct methods of enrichment were used followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). These included: immunoprecipitation (IP) of endogenous ADAR1, IP of Strep II-tagged ADAR1, and proximity labeling using BioID. Individual ADAR1 isoforms (p110 and p150) and their respective dsRNA binding-deficient mutants were created to discern isoform-specific and dsRNA-dependent interactions. Altogether, our results reveal a comprehensive ADAR1 interaction map, identifying both known and novel partners, and highlighting the isoform-specific and dsRNA-binding-dependent nature of ADAR1 interactions. Under IFN stimulation, ADAR1's interaction spectrum encompasses viral replication inhibitors and LINE-1 regulators. Mimicking viral infection with HMW poly(I:C) changed the proximal network of proteins for both isoforms. Our findings provide new insights into ADAR1's roles and its dynamic during IFN response.
2024-12-05 | PXD049681 | Pride
Project description:Adenosine deaminase acting on RNA 1 (ADAR1), is an enzyme that catalyzes the conversion of adenosine to inosine in double-stranded RNA, a process critical for regulation of innate immune response and distinguishing between ‘self and non-self RNA’. It is expressed as two isoforms: nucleolar p110 and cytoplasmic, interferon (IFN)-inducible, p150. The interactome of the p110 under steady-state conditions is well-studied; however, less is known about the interactions of the p150 isoform, particularly during IFN response. To elucidate ADAR1's protein interactions during IFN stimulation, alongside steady-state conditions, three distinct methods of enrichment were used followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). These included: immunoprecipitation (IP) of endogenous ADAR1, IP of Strep II-tagged ADAR1, and proximity labeling using BioID. Individual ADAR1 isoforms (p110 and p150) and their respective dsRNA binding-deficient mutants were created to discern isoform-specific and dsRNA-dependent interactions. Altogether, our results reveal a comprehensive ADAR1 interaction map, identifying both known and novel partners, and highlighting the isoform-specific and dsRNA-binding-dependent nature of ADAR1 interactions. Under IFN stimulation, ADAR1's interaction spectrum encompasses viral replication inhibitors and LINE-1 regulators. Mimicking viral infection with HMW poly(I:C) changed the proximal network of proteins for both isoforms. Our findings provide new insights into ADAR1's roles and its dynamic during IFN response.
2024-12-05 | PXD049684 | Pride
Project description:Adenosine deaminase acting on RNA 1 (ADAR1), is an enzyme that catalyzes the conversion of adenosine to inosine in double-stranded RNA, a process critical for regulation of innate immune response and distinguishing between ‘self and non-self RNA’. It is expressed as two isoforms: nucleolar p110 and cytoplasmic, interferon (IFN)-inducible, p150. The interactome of the p110 under steady-state conditions is well-studied; however, less is known about the interactions of the p150 isoform, particularly during IFN response. To elucidate ADAR1's protein interactions during IFN stimulation, alongside steady-state conditions, three distinct methods of enrichment were used followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). These included: immunoprecipitation (IP) of endogenous ADAR1, IP of Strep II-tagged ADAR1, and proximity labeling using BioID. Individual ADAR1 isoforms (p110 and p150) and their respective dsRNA binding-deficient mutants were created to discern isoform-specific and dsRNA-dependent interactions. Altogether, our results reveal a comprehensive ADAR1 interaction map, identifying both known and novel partners, and highlighting the isoform-specific and dsRNA-binding-dependent nature of ADAR1 interactions. Under IFN stimulation, ADAR1's interaction spectrum encompasses viral replication inhibitors and LINE-1 regulators. Mimicking viral infection with HMW poly(I:C) changed the proximal network of proteins for both isoforms. Our findings provide new insights into ADAR1's roles and its dynamic during IFN response.
2024-12-08 | PXD049991 | Pride
Project description:The antiviral defense in vertebrates requires the innate immune system to sense foreign “non-self” nucleic acids while avoiding “self” nucleic acids, which is accomplished by an intricate system. Cellular double-stranded RNAs (dsRNAs) are edited by the RNA editing enzyme ADAR1 to prevent their dsRNA structure pattern from being recognized as viral dsRNA. Lack of RNA editing by ADAR1 enables activation of MDA5, a cytosolic dsRNA sensor, by cellular dsRNA. Additional RNA editing- independent functions of ADAR1 have been proposed, but the specific mechanism remains elusive. Here we demonstrate that RNA binding by ADAR1, independent of its editing activity, restricts the activation of PKR, another cytosolic dsRNA sensor, by cellular dsRNA. Mechanistically, the loss of ADAR1 editing caused MDA5 activation to induce interferon signaling, while a lack of ADAR1 protein or its dsRNA binding ability led to PKR activation, with subsequent stress granule formation and proliferation arrest. Based on these findings we rescued the Adar1−/− mice from embryonic lethality to adulthood by deleting both MDA5 and PKR, in contrast to the limited rescue of Adar1−/− mice by removing MDA5 or PKR alone. Our findings reveal a multifaceted contribution of ADAR1 in regulating the immunogenicity of “self” dsRNAs. Furthermore, ADAR1 is an immuno-oncology target for drug development, and the separation of ADAR1’s RNA editing and binding functions provides mechanistic insights for such developments.
2023-10-03 | GSE198386 | GEO
Project description:Epigenetic therapies that alter DNA- and/or histone modifications facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events that include functional inactivation of canonical tumor suppressor proteins also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize patient-derived premalignant lesions of the fallopian tube along with syngeneic mouse models of epithelial ovarian cancer to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss disrupts constitutive heterochromatin to permit transcription of immunogenic repetitive elements capable of activating viral mimicry responses. While acute viral mimicry activation diminishes cell fitness, chronic viral mimicry activation following p53 loss promotes epigenetic reprogramming that increases tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity as a pro-survival adaptation. This selection process we describe as ‘viral mimicry conditioning’ can be partially attenuated by the reverse transcriptase inhibitor 3TC to delay spontaneous tumorigenesis. Altogether, these results reveal that viral mimicry conditioning following p53 loss selects for diminished cell immunogenicity to promote immune evasion upon cancer initiation. Disruption of viral mimicry conditioning during cancer initiation may represent a pharmacological target for early cancer interception.
2024-12-10 | GSE216941 | GEO
Project description:Epigenetic therapies that alter DNA- and/or histone modifications facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events that include functional inactivation of canonical tumor suppressor proteins also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize patient-derived premalignant lesions of the fallopian tube along with syngeneic mouse models of epithelial ovarian cancer to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss disrupts constitutive heterochromatin to permit transcription of immunogenic repetitive elements capable of activating viral mimicry responses. While acute viral mimicry activation diminishes cell fitness, chronic viral mimicry activation following p53 loss promotes epigenetic reprogramming that increases tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity as a pro-survival adaptation. This selection process we describe as ‘viral mimicry conditioning’ can be partially attenuated by the reverse transcriptase inhibitor 3TC to delay spontaneous tumorigenesis. Altogether, these results reveal that viral mimicry conditioning following p53 loss selects for diminished cell immunogenicity to promote immune evasion upon cancer initiation. Disruption of viral mimicry conditioning during cancer initiation may represent a pharmacological target for early cancer interception.
2024-12-10 | GSE216640 | GEO