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DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE209777 | GEO | 2023/08/22

REPOSITORIES: GEO

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DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Project description:Immunotherapies targeting cancer-specific immunogenic neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies could synergize with immunotherapies, mediating the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here we use RNA sequencing from cancer cells treated with DNMT and/or HDAC inhibitors, to assemble a de novo transcriptome and identified 3,023 ERV-derived, treatment-induced novel polA+ transcripts (TINPATs), encoding for 61,426 novel open reading frames. We further demonstrate, using human leukocyte antigen immunopeptidomics, the existence of treatment-induced neoepitopes (t-neoepitopes) derived from TINPATs. We demonstrated the potential of the identified t-neoepitopes to elicit an immunogenic T-cell response and cancer cell killing. The presence of t-neoepitopes was further verified in AML patient samples 48 h and /96 h after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight a novel mechanism of ERV-derived neoantigens in epigenetic and immune therapies.

2023-09-13 | PXD035748 | Pride

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Project description:Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated bythe de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitors (DNMTi) and/or Histone deacetylase transferase inhibitors (HDACi), to assemble a de novo transcriptome and identified 3,023 ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs), encoding for 61,426 open reading frames. Using Immunopeptidomics, we further demonstrate the human leukocyte antigen (HLA) presentation of treatment-induced neoepitopes (t-neoepitopes) derived from TINPATs. We illustrate the potential of the identified t-neoepitopes to elicit a T-cell response and cancer cell killing. The presence of t-neoepitopes was further verified in AML patient samples 48/96 h after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight a novel mechanism of ERV-derived neoantigens in epigenetic and immune therapies.

2023-08-18 | PXD035750 | Pride

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [Ribo-Seq]

Project description:To investigate the effect of Decitabine and SB939 treatment on the expression of endoretroviral elements. We treated NCI-H1299 cells with DMSO or a combination of Decitabine and SB939 and performed Ribo-seq. This data was used to identify novel ORFs expressed from endoretroviral elements derived transcripts.

2023-08-22 | GSE209776 | GEO

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [RNA-Seq]

Project description:To investigate the effect of Decitabine and SB939 treatment on the expression of endoretroviral elements. We treated 9 cell lines with DMSO, Decitabine, SB939 or a combination of Decitabine and SB939 and performed RNA-seq. This data was used to generate a denovo transcriptome assembly to identify novel mRNAs expressed from endoretroviral elements.

2023-08-22 | GSE209772 | GEO

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Project description:DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

| PRJNA862442 | ENA

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [Ribo-Seq]

Project description:DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [Ribo-Seq]

| PRJNA862448 | ENA

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [RNA-Seq]

Project description:DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [RNA-Seq]

| PRJNA862388 | ENA

Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors.

Project description:Inhibitors of DNA methyltransferases (DNMTis) or histone deacetylases (HDACis) are epigenetic drugs which are investigated since decades. Several have been approved and are applied in the treatment of hematopoietic and lymphatic malignancies, although their mode of action has not been fully understood. Two recent findings improved mechanistic insights: i) activation of human endogenous retroviral elements (HERVs) with concomitant synthesis of double-stranded RNAs (dsRNAs), and ii) massive activation of promoters from long terminal repeats (LTRs) which originated from past HERV invasions. These dsRNAs activate an antiviral response pathway followed by apoptosis. LTR promoter activation leads to synthesis of non-annotated transcripts potentially encoding novel or cryptic proteins. Here, we discuss the current knowledge of the molecular effects exerted by epigenetic drugs with a focus on DNMTis and HDACis. We highlight the role in LTR activation and provide novel data from both in vitro and in vivo epigenetic drug treatment.

| S-EPMC6056222 | biostudies-literature

Non-retroviral Endogenous Viral Element Limits Cognate Virus Replication in Aedes aegypti Ovaries.

Project description:Endogenous viral elements (EVEs) are viral sequences integrated in host genomes. A large number of non-retroviral EVEs was recently detected in Aedes mosquito genomes, leading to the hypothesis that mosquito EVEs may control exogenous infections by closely related viruses. Here, we experimentally investigated the role of an EVE naturally found in Aedes aegypti populations and derived from the widespread insect-specific virus, cell-fusing agent virus (CFAV). Using CRISPR-Cas9 genome editing, we created an Ae. aegypti line lacking the CFAV EVE. Absence of the EVE resulted in increased CFAV replication in ovaries, possibly modulating vertical transmission of the virus. Viral replication was controlled by targeting of viral RNA by EVE-derived P-element-induced wimpy testis-interacting RNAs (piRNAs). Our results provide evidence that antiviral piRNAs are produced in the presence of a naturally occurring EVE and its cognate virus, demonstrating a functional link between non-retroviral EVEs and antiviral immunity in a natural insect-virus interaction.

| S-EPMC7522710 | biostudies-literature

Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells.

Project description:Transposable elements comprise roughly 40% of mammalian genomes. They have an active role in genetic variation, adaptation and evolution through the duplication or deletion of genes or their regulatory elements, and transposable elements themselves can act as alternative promoters for nearby genes, resulting in non-canonical regulation of transcription. However, transposable element activity can lead to detrimental genome instability, and hosts have evolved mechanisms to silence transposable element mobility appropriately. Recent studies have demonstrated that a subset of transposable elements, endogenous retroviral elements (ERVs) containing long terminal repeats (LTRs), are silenced through trimethylation of histone H3 on lysine 9 (H3K9me3) by ESET (also known as SETDB1 or KMT1E) and a co-repressor complex containing KRAB-associated protein 1 (KAP1; also known as TRIM28) in mouse embryonic stem cells. Here we show that the replacement histone variant H3.3 is enriched at class I and class II ERVs, notably those of the early transposon (ETn)/MusD family and intracisternal A-type particles (IAPs). Deposition at a subset of these elements is dependent upon the H3.3 chaperone complex containing α-thalassaemia/mental retardation syndrome X-linked (ATRX) and death-domain-associated protein (DAXX). We demonstrate that recruitment of DAXX, H3.3 and KAP1 to ERVs is co-dependent and occurs upstream of ESET, linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of IAPs. Our study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells.

| S-EPMC4509593 | biostudies-literature

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