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SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence

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

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE167367 | GEO | 2021/03/17

REPOSITORIES: GEO

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SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence [RNA-Seq]

Project description:We analyzed ChIP-seq, chromatin accessibility and RNA-seq across mouse esophageal squamous organoids and human esophageal squamous cell cancer

2021-03-17 | GSE167365 | GEO

SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence [ChIP-Seq, ATAC-Seq]

Project description:We analyzed ChIP-seq, chromatin accessibility and RNA-seq across mouse esophageal squamous organoids and human esophageal squamous cell cancer

2021-03-17 | GSE167366 | GEO

SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence

Project description:SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence

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SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence [RNA-Seq]

Project description:SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence [RNA-Seq]

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SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence [ChIP-Seq, ATAC-Seq]

Project description:SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence [ChIP-Seq, ATAC-Seq]

| PRJNA704401 | ENA

Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence.

Project description:Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities.

| S-EPMC9124436 | biostudies-literature

RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.

Project description:Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) enzymes. In addition to RNA editing, additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1, we generated mice with an editing-deficient knock-in mutation (Adar1(E861A), where E861A denotes Glu(861)?Ala(861)). Adar1(E861A/E861A) embryos died at ~E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)-sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3' untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of Adar1(E861A/E861A) were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts.

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Endogenous retroviral pathogenesis in lupus.

Project description:Genetic and environmental factors influence the development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERVs) are proposed as a molecular link between the human genome and environmental factors, such as viruses, in lupus pathogenesis.The HRES-1 human ERV encodes a 28-kD nuclear autoantigen and a 24-kD small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a target of cross-reactive antiviral antibodies, whereas HRES-1/Rab4 regulates the surface expression of CD4 via endosome recycling. The tat gene of HIV-1 induces the expression of HRES-1/Rab4, which in turn downregulates expression of CD4 and susceptibility to reinfection by HIV-1. HRES-1/Rab4 is overexpressed in lupus T cells where it correlates with increased recycling of CD4 and CD3 and contributes to downregulation of CD3/TCRzeta via lysosomal degradation. Chilblain lupus has been linked to the deficiency of 3'-5' repair exonuclease Trex1 that metabolizes DNA reverse-transcribed from ERV. Trex1 deficiency or blocked integration of ERV-encoded DNA also promotes lupus in murine models.ERV proteins may trigger lupus through structural and functional molecular mimicry, whereas the accumulation of ERV-derived nucleic acids stimulates interferon and anti-DNA antibody production in SLE.

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SOX2 reprograms resident astrocytes into neural progenitors in the adult brain.

Project description:Glial cells can be in vivo reprogrammed into functional neurons in the adult CNS; however, the process by which this reprogramming occurs is unclear. Here, we show that a distinct cellular sequence is involved in SOX2-driven in situ conversion of adult astrocytes to neurons. This includes ASCL1(+) neural progenitors and DCX(+) adult neuroblasts (iANBs) as intermediates. Importantly, ASCL1 is required, but not sufficient, for the robust generation of iANBs in the adult striatum. These progenitor-derived iANBs predominantly give rise to calretinin(+) interneurons when supplied with neurotrophic factors or the small-molecule valproic acid. Patch-clamp recordings from the induced neurons reveal subtype heterogeneity, though all are functionally mature, fire repetitive action potentials, and receive synaptic inputs. Together, these results show that SOX2-mediated in vivo reprogramming of astrocytes to neurons passes through proliferative intermediate progenitors, which may be exploited for regenerative medicine.

| S-EPMC4437485 | biostudies-literature

Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown.

Project description:Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.

| S-EPMC5831367 | biostudies-literature

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