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Endogenous retroviruses are a source of oncogenic enhancers in acute myeloid leukemia [RNA-Seq]

ABSTRACT: Endogenous retroviruses (ERVs) and other transposons can act as tissue-specific regulators of gene expression in cis, with potential to affect biological processes. In cancer, epigenetic alterations and transcription factor misregulation may uncover the regulatory potential of typically repressed ERVs, which could contribute to tumour evolution and progression. Here, we asked whether transposons help to rewire oncogenic transcriptional circuits in acute myeloid leukaemia (AML). Using epigenomic data from both primary cells and cell lines, we have identified six ERV families that are frequently found in an open chromatin state in AML when compared to differentiated myeloid cells. A subset of these AML-associated ERVs harbour enhancer-specific histone modifications, and are bound by transcription factors that play key roles in haematopoiesis and in the pathogenesis of AML. Using CRISPR-mediated genetic and epigenetic editing, we have established causal links between ERV deregulation in AML and expression changes of adjacent genes. Finally, we show that deletion and epigenetic silencing of an ERV associated with the APOC1 gene leads to growth suppression by inducing apoptosis in leukemia cell lines. Our results suggest that ERV derepression provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive oncogenic phenotypes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136763 | GEO | 2019/09/04

REPOSITORIES: GEO

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Endogenous retroviruses are a source of oncogenic enhancers in acute myeloid leukemia [ChIP-Seq]

Project description:Endogenous retroviruses (ERVs) and other transposons can act as tissue-specific regulators of gene expression in cis, with potential to affect biological processes. In cancer, epigenetic alterations and transcription factor misregulation may uncover the regulatory potential of typically repressed ERVs, which could contribute to tumour evolution and progression. Here, we asked whether transposons help to rewire oncogenic transcriptional circuits in acute myeloid leukaemia (AML). Using epigenomic data from both primary cells and cell lines, we have identified six ERV families that are frequently found in an open chromatin state in AML when compared to differentiated myeloid cells. A subset of these AML-associated ERVs harbour enhancer-specific histone modifications, and are bound by transcription factors that play key roles in haematopoiesis and in the pathogenesis of AML. Using CRISPR-mediated genetic and epigenetic editing, we have established causal links between ERV deregulation in AML and expression changes of adjacent genes. Finally, we show that deletion and epigenetic silencing of an ERV associated with the APOC1 gene leads to growth suppression by inducing apoptosis in leukemia cell lines. Our results suggest that ERV derepression provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive oncogenic phenotypes.

2019-09-04 | GSE136759 | GEO

Endogenous retroviruses are a source of oncogenic enhancers in acute myeloid leukemia [DNase-Seq]

2019-09-04 | GSE136760 | GEO

SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes [RNA-Seq]

Project description:Genome stability relies on epigenetic mechanisms that enforce repression of endogenous retroviruses (ERVs). Current evidence suggests that distinct chromatin-based mechanisms repress ERVs in cells of embryonic origin (histone methylation-dominant) versus more differentiated cells (DNA methylation-dominant). However, the latter aspect of this model has not been tested. Remarkably, and in contrast to the prevailing model, we find that repressive histone methylation catalyzed by the enzyme SETDB1 is critical for suppression of specific ERV families and exogenous retroviruses in committed B-lineage cells from adult mice. The profile of ERV activation in SETDB1-deficient B cells is distinct from that observed in corresponding embryonic tissues, despite the loss of repressive chromatin modifications at all ERVs. We provide evidence that, upon loss of SETDB1, ERVs are activated in a lineage-specific manner depending on the set of transcription factors available to target proviral regulatory elements. These findings have important implications for genome stability in somatic cells, as well as the interface between epigenetic repression and viral latency. Expression profiling and bisulfite PCR sequencing in Setdb1 C/C and Setdb1 D/D pro-B cells

2015-07-03 | E-GEOD-69464 | biostudies-arrayexpress

Endogenous retrovirus MER50-derived enhancers confer the transcriptional regulation of human trophoblast syncytialization [RNA-Seq]

Project description:Multinucleated syncytiotrophoblasts (STBs), which are in direct contact with maternal blood, constitute the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. However, the genetic and epigenetic regulatory mechanisms governing trophoblast syncytialization remain largely elusive. We delineate that endogenous retroviruses (ERVs), which have been exapted as regulatory sequences for specific functional adaptations in placenta, profoundly rewire transcriptional program of trophoblast syncytialization. Here, we first determined dynamic bivalent ERV-derived enhancers with dual occupancy of H3K9me3 and H3K27ac in human trophoblast stem cells (hTSCs), which emerge as cell specific regulators of gene expression with markedly resolved H3K9me3 during differentiation towards STBs. Of note, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of STB-specific genes. Importantly, depletions of MER50 elements adjacent to several STB genes, including MFSD2A, TNFAIP2 and RAI14, significantly attenuated their expression concomitant to dysregulated syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional program accounting for human trophoblast syncytialization, which sheds light on novel epigenetic regulatory mechanisms underlying placental development.

2023-02-03 | GSE209976 | GEO

Endogenous retrovirus MER50-derived enhancers confer the transcriptional regulation of human trophoblast syncytialization [ChIP-Seq]

2023-02-03 | GSE209975 | GEO

Rescue of Tet2 KO ES cells in primed or naïve state

Project description:Endogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET-dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos. We used naïve ESCs to investigate the role of SETDB1 in ERV regulation and, in particular, its relationship with TET-mediated DNA demethylation. Naïve ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We found that, in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, however, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these transposons indirectly.

2017-09-25 | GSE100863 | GEO

SETDB1 depletion in primed or naïve ES cells

2017-09-25 | GSE94444 | GEO

Activation of endogenous retroviruses during brain development causes neuroinflammation

Project description:Endogenous retroviruses (ERVs) make up a large fraction of mammalian genome and are thought to contribute to human disease, including brain disorders. Aberrant activation of ERVs constitute a potential trigger for neuroinflammation, but mechanistic insight into this phenomenon remains unclear. Using CRISPR/Cas9-based gene disruption of the epigenetic co-repressor protein Trim28, we found a dynamic H3K9me3-dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons. In vivo disruption of Trim28 in cortical NPCs during brain development resulted in viable offspring expressing high levels of ERVs in excitatory neurons in the adult brain of mice. Neuronal ERV expression was linked to inflammation, including activated microglia, and aggregates of ERV-derived proteins. This study demonstrates that brain development is a critical period for the silencing of ERVs and provides causal in vivo evidence demonstrating that transcriptional activation of ERV in neurons results in neuroinflammation.

2021-02-24 | GSE154196 | GEO

Ssrp1 co-immunoprecipitation and mass spectrometry

Project description:Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.

2020-08-24 | PXD017351 | Pride

RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells [RNA-Seq]

Project description:Ten-eleven translocation (TET) proteins play key roles in regulating the methylation status of DNA through oxidizing methylcytosines (5mC), generating 5-hydroxymethylcytosines (5hmC) that can both serve as stable epigenetic marks and participate in active demethylation. Here we show that TET2 is recruited by the RNA-binding protein Paraspeckle component 1 (PSPC1) through transcriptionally active loci, including endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) have been co-opted by mammalian genomes as stage- and tissue-specific transcriptional regulatory modules. We find that PSPC1 and TET2 contribute to ERV and ERV-associated gene regulation by both transcriptional repression via histone deacetylases and post-transcriptional destabilization of ERV RNAs through 5hmC modification. Our findings provide evidence for a functional role of transcriptionally active ERVs as specific docking sites for RNA epigenetic modulation and gene regulation.

2018-02-26 | GSE103267 | GEO

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