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Grainyhead-like-2, an epithelial master programmer, promotes interferon induction and suppresses breast cancer recurrence [RNA-Seq]

ABSTRACT: Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes the type-I and -III interferon responses to double-strand RNA, an important ligand for immune rejection of tumors via interferons. The positive effects of GRHL2 were mediated by enhanced IRF3 and relA/NF-kB activation, upregulation of IRF1, and a functional GRHL2 binding site identified in the IFNL1 promoter. In addition, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241852 | GEO | 2024/04/26

REPOSITORIES: GEO

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Grainyhead-like-2, an epithelial master programmer, promotes interferon induction and suppresses breast cancer recurrence [ATAC-seq]

Project description:Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes the type-I and -III interferon responses to double-strand RNA, an important ligand for immune rejection of tumors via interferons. The positive effects of GRHL2 were mediated by enhanced IRF3 and relA/NF-kB activation, upregulation of IRF1, and a functional GRHL2 binding site identified in the IFNL1 promoter. In addition, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.

2024-04-26 | GSE241853 | GEO

Identical transcriptome reprograming by interferon lambda 3 and 4 and its absence in IFNLR1 or IL10R2 deficient cells rules out the IFNL4 non-canonical signaling hypothesis

Project description:Lambda interferons IFNL1-3 mediate antiviral immunity by inducing interferon sensitive genes (ISGs) in epithelial tissues. Contrarily, a variant creating the functional gene IFNL4 is associated with impaired clearance of hepatitis C virus (HCV) despite of higher liver expression of ISGs in untreated HCV patients. We aimed to explore IFNL4 signaling mechanism by comparing expression profiles from human hepatic cell line clones with genetic modifications influencing the ISG signaling pathway (IFNLR1/IL10R2 knockouts, IFNL4/IFNL3 expression stimulation by transfection).

2021-12-31 | E-MTAB-8916 | biostudies-arrayexpress

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Project description:Aim: Identify molecular pathways controlling palate closure Methods: First pharygneal arch of wild-type and Grhl2-/- e10.5 moues embryos was subjected to RNAseq Results: Grhl2-/- PA1 displayed a shift from epithelial to mesenchymal gene expression Conclusions: Grhl2 maintains epithelial cellular identity during palate closure

2020-03-03 | GSE106130 | GEO

Grhl2 regulated genes in the mouse lung epithelial MLE15 cell line

Project description:The Grainyhead family of transcription factors controls morphogenesis and differentiation of epithelial cell layers in multicellular organisms by regulating cell junction- and proliferation-related genes. Grainyhead-like 2 (Grhl2) is expressed in developing mouse lung epithelium and is required for normal lung organogenesis. The specific epithelial cells expressing Grhl2 and the genes regulated by Grhl2 in normal lungs are mostly unknown. In these studies, we identified the NK2 homeobox 1 transcription factor (Nkx2-1) as a direct transcriptional target of Grhl2. By binding and transcriptional assays, and by confocal microscopy we showed that these two transcription factors form a positive feed-back loop in vivo and in cell lines, and are co-expressed in lung bronchiolar and alveolar type II cells. The morphological changes observed in flattening lung alveolar type II cells in culture are associated with down-regulation of Grhl2 and Nkx2-1. Reduction of Grhl2 in lung epithelial cell lines results in lower expression levels of Nkx2-1 and of known Grhl2 target genes. By microarray analysis we identified that in addition to Cadherin1 and Claudin4, Grhl2 regulates other cell interaction genes such as semaphorins and their receptors, which also play a functional role in developing lung epithelium. Impaired collective cell migration observed in Grhl2 knockdown cell monolayers is associated with reduced expression of these genes and may contribute to the altered epithelial phenotype reported in Grhl2 mutant mice. Thus, Grhl2 functions at the nexus of a novel regulatory network, connecting lung epithelial cell identity, migration and cell-cell interactions. To identify genes regulated by GRHL2 in lung epithelial cells, we performed cDNA microarray analyses in MLE15 cells transduced with Grhl2-shRNA and compared to a non-silencing control. Independent transductions of MLE15 cells using Grhl2-shRNA (n=3) and a non-silencing control (n=2) were analyzed.

2012-09-10 | E-GEOD-40729 | biostudies-arrayexpress

Grhl2 regulated genes in the mouse lung epithelial MLE15 cell line

2012-09-10 | GSE40729 | GEO

Population context drives cell-to-cell variability in interferon response in epithelial cells

Project description:Isogenic cells respond in a heterogeneous manner to interferon. Using a micropatterning approach combined with high-content imaging and spatial analyses, we characterized how the population context (position of a cell with respect to neighboring cells) of epithelial cells affects single cell response to interferons. We identified that cells at the edge of cellular colonies are more responsive than cells embedded within colonies. We determined that this spatial heterogeneity in interferon response resulted from the polarized basolateral interferon receptor distribution, making cells located in the center of cellular colonies less responsive to ectopic interferon stimulation. This was conserved across cell lines and primary cells originated from epithelial tissues. Finally, we demonstrated that this population context-driven cell-to-cell variability influences the outcome of viral infection, as cells embedded within cellular colonies are not protected by interferons and therefore more susceptible to infection. Our data highlights that the behavior of isolated cells does not directly translate to their behavior in a population, placing the population context as one important factor influencing cell-to-cell heterogeneity during interferon response in epithelial cells.

2024-02-07 | PXD047936 | Pride

Distinct immune responses to type I and III interferons are regulated by interferon regulatory factor 1

Project description:Distinct immune responses to type I and III interferons are regulated by interferon regulatory factor 1

| PRJNA474093 | ENA

Ku70 Is a Novel Cytosolic DNA Sensor that Induces Type-III Rather than Type-I IFN

Project description:Cytosolic foreign DNA is detected by pattern recognition receptors and mainly induces Type-I IFN production. We found that transfection of different types of DNA into various untreated cells induces Type-III IFN (IFN-lambda1) rather than Type-I IFN, indicating the presence of uncharacterized DNA sensor(s). A pull-down assay using cytosolic proteins identified that Ku70 and Ku80 are the DNA binding proteins. The knockdown studies and the reporter assay revealed that Ku70 is a novel DNA sensor inducing the IFN-lambda1 activation. The functional analysis of IFNL1 promoter revealed that PRDI and ISRE sites are predominantly involved in the DNA-mediated IFNL1 activation. A pull-down assay using nuclear proteins demonstrated that the IFN-lambda1 induction is associated with the activation of IRF-1 and IRF-7. This is the first report of a specific induction of Type-III rather than Type-I IFN and of Ku70 that plays a key role in the activation of innate immune responses.

2011-01-29 | GSE26944 | GEO

Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells

Project description:Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, the human cytomegalovirus (CMV). Human pDCs responded poorly to free CMV but strongly to live CMV-infected fibroblasts, in a process that involved integrin-mediated adhesion, transfer of viral DNA to pDCs and its recognition through TLR9. Compared to transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of type I (IFN-I) and type III (IFN-III) interferons, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells that are critical for CMV control. Finally, patients with CMV viremia harbored phenotypically activated pDCs and increased levels of IFN-I and IFN-III in circulation. Thus, recognition of live infected cells is a common mechanism of virus detection by pDCs that elicits a unique antiviral response program.

2021-03-01 | GSE163707 | GEO

Ku70 Is a Novel Cytosolic DNA Sensor that Induces Type-III Rather than Type-I IFN

2011-01-29 | E-GEOD-26944 | biostudies-arrayexpress

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