Transcriptomic analysis of CIC and ATXN1L in normal human astrocytes
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ABSTRACT:
PROVIDER: PRJNA589862 | ENA |
REPOSITORIES: ENA
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Project description:Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through activation of the MAPK signalling cascade and derepression of oncogenic ETS transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in developmental and disease contexts to facilitate the repression of CIC target genes. To further investigate this relationship, we performed functional in vitro studies utilizing ATXN1LKO and CICKO human cell lines and characterized a reciprocal functional relationship between CIC and ATXN1L.
2020-03-31 | GSE140471 | GEO
Project description:CIC has recently been implicated as a negative prognostic factor in multiple cancers. CIC and ATXN1L have been reported as interactors in several cellular contexts including development and disease state. To investigate the relationship between CIC and ATXN1L on a transcriptomic level, CIC-KO and ATXN1L-KO cell lines were generated. Gene expression profiling of CIC-KO and ATXN1L-KO cell lines was performed by microarray and differentially expressed genes were compared. We found a high degree of overlap in differentially expressed genes in CIC-KO and ATXN1L-KO suggesting loss of either interacting partner to lead to similar transcriptomic changes.
2017-09-30 | GSE103514 | GEO
Project description:CIC has recently been implicated as a negative prognostic factor in multiple cancers. CIC and ATXN1L have been reported as interactors in several cellular contexts including development and disease state. To investigate the relationship between CIC and ATXN1L on a transcriptomic level, CIC-KO and ATXN1L-KO cell lines were generated. Gene expression profiling of CIC-KO and ATXN1L-KO cell lines was performed by microarray and differentially expressed genes were compared. We found a high degree of overlap in differentially expressed genes in CIC-KO and ATXN1L-KO suggesting loss of either interacting partner to lead to similar transcriptomic changes.
2017-09-30 | GSE103513 | GEO
Project description:CIC and ATXN1L knockout gene expression data
| PRJNA401478 | ENA
Project description:Capicua (CIC)’s transcriptional repressor function is implicated in neurodevelopment and in oligodendroglioma (ODG) aetiology. However, CIC’s role in these contexts remains obscure, primarily from our currently limited knowledge regarding its biological functions. Moreover, CIC mutations in ODG invariably co-occur with a neomorphic IDH1/2 mutation, yet the functional relationship between these two genetic events is unknown. Here, we analysed models derived from an E6/E7/hTERT-immortalized (i.e. p53- and RB-deficient) normal human astrocyte cell line. To examine the consequences of CIC loss, we compared transcriptomic and epigenomic profiles between CIC wildtype and knockout cell lines, with and without mutant IDH1 expression. Our analyses revealed dysregulation of neurodevelopmental genes in association with CIC loss. CIC ChIP-seq was also performed to expand upon the currently limited ensemble of known CIC target genes. Among the newly identified direct CIC target genes were EPHA2 and ID1, whose functions are linked to neurodevelopment and the tumourigenicity of in vivo glioma tumour models. NFIA, a known mediator of gliogenesis, was discovered to be uniquely overexpressed in double mutant cells (CIC-knockout + IDH1-mutant). These results identify neurodevelopment and specific genes within this context as candidate targets through which CIC alterations may contribute to the progression of IDH-mutant gliomas.
2021-12-01 | GSE189857 | GEO
Project description:Capicua (CIC)’s transcriptional repressor function is implicated in neurodevelopment and in oligodendroglioma (ODG) aetiology. However, CIC’s role in these contexts remains obscure, primarily from our currently limited knowledge regarding its biological functions. Moreover, CIC mutations in ODG invariably co-occur with a neomorphic IDH1/2 mutation, yet the functional relationship between these two genetic events is unknown. Here, we analysed models derived from an E6/E7/hTERT-immortalized (i.e. p53- and RB-deficient) normal human astrocyte cell line. To examine the consequences of CIC loss, we compared transcriptomic and epigenomic profiles between CIC wildtype and knockout cell lines, with and without mutant IDH1 expression. Our analyses revealed dysregulation of neurodevelopmental genes in association with CIC loss. CIC ChIP-seq was also performed to expand upon the currently limited ensemble of known CIC target genes. Among the newly identified direct CIC target genes were EPHA2 and ID1, whose functions are linked to neurodevelopment and the tumourigenicity of in vivo glioma tumour models. NFIA, a known mediator of gliogenesis, was discovered to be uniquely overexpressed in double mutant cells (CIC-knockout + IDH1-mutant). These results identify neurodevelopment and specific genes within this context as candidate targets through which CIC alterations may contribute to the progression of IDH-mutant gliomas.
2021-12-01 | GSE189860 | GEO
Project description:Capicua (CIC)’s transcriptional repressor function is implicated in neurodevelopment and in oligodendroglioma (ODG) aetiology. However, CIC’s role in these contexts remains obscure, primarily from our currently limited knowledge regarding its biological functions. Moreover, CIC mutations in ODG invariably co-occur with a neomorphic IDH1/2 mutation, yet the functional relationship between these two genetic events is unknown. Here, we analysed models derived from an E6/E7/hTERT-immortalized (i.e. p53- and RB-deficient) normal human astrocyte cell line. To examine the consequences of CIC loss, we compared transcriptomic and epigenomic profiles between CIC wildtype and knockout cell lines, with and without mutant IDH1 expression. Our analyses revealed dysregulation of neurodevelopmental genes in association with CIC loss. CIC ChIP-seq was also performed to expand upon the currently limited ensemble of known CIC target genes. Among the newly identified direct CIC target genes were EPHA2 and ID1, whose functions are linked to neurodevelopment and the tumourigenicity of in vivo glioma tumour models. NFIA, a known mediator of gliogenesis, was discovered to be uniquely overexpressed in double mutant cells (CIC-knockout + IDH1-mutant). These results identify neurodevelopment and specific genes within this context as candidate targets through which CIC alterations may contribute to the progression of IDH-mutant gliomas.
2021-12-01 | GSE189858 | GEO
Project description:Capicua (CIC)’s transcriptional repressor function is implicated in neurodevelopment and in oligodendroglioma (ODG) aetiology. However, CIC’s role in these contexts remains obscure, primarily from our currently limited knowledge regarding its biological functions. Moreover, CIC mutations in ODG invariably co-occur with a neomorphic IDH1/2 mutation, yet the functional relationship between these two genetic events is unknown. Here, we analysed models derived from an E6/E7/hTERT-immortalized (i.e. p53- and RB-deficient) normal human astrocyte cell line. To examine the consequences of CIC loss, we compared transcriptomic and epigenomic profiles between CIC wildtype and knockout cell lines, with and without mutant IDH1 expression. Our analyses revealed dysregulation of neurodevelopmental genes in association with CIC loss. CIC ChIP-seq was also performed to expand upon the currently limited ensemble of known CIC target genes. Among the newly identified direct CIC target genes were EPHA2 and ID1, whose functions are linked to neurodevelopment and the tumourigenicity of in vivo glioma tumour models. NFIA, a known mediator of gliogenesis, was discovered to be uniquely overexpressed in double mutant cells (CIC-knockout + IDH1-mutant). These results identify neurodevelopment and specific genes within this context as candidate targets through which CIC alterations may contribute to the progression of IDH-mutant gliomas.
2021-12-01 | GSE189859 | GEO
Project description:The receptor tyrosine kinase (RTK)/Extracellular Signal-Regulated Kinase (ERK) signaling pathway controls cell proliferation, differentiation, and survival. How ERK activation is relayed to its phosphorylation targets is not well understood. The transcriptional repressor Capicua (Cic) has emerged as a key target for ERK-mediated downregulation in Drosophila and mammals, and mutations in human CIC result in cancer and neurological diseases. Phosphorylation by ERK is critical for Cic downregulation, but the identities of phosphosites in Drosophila Cic are unknown. Here, we identify sites of phosphorylation in Cic that are directly targeted by ERK and validate their developmental functions in vivo using mutant Cic variants. Cic phosphosites are distributed throughout the length of the protein, and a group of centrally located sites appears to have a primary role in Cic downregulation. Cic mutated in 20 high-confidence sites behaves as a “super-repressor” in vivo that is largely insensitive to ERK-mediated downregulation, despite fully retaining the ability to bind to ERK. No single site is sufficient to turn off Cic activity; instead, we find that ERK must phosphorylate multiple sites in Cic simultaneously to achieve full downregulation. This multisite phosphorylation likely targets phosphodegrons that are recognized by ubiquitin ligases such as Ago/FBXW7 and contributes to Cic degradation. This study advances our understanding of the molecular mechanisms of signal interpretation downstream of the RTK/ERK signaling network.
2026-03-16 | PXD066179 | Pride
Project description:Early detection of viral infection and rapid activation of host antiviral defenses are critical for limiting viral replication and spread. At a cellular level, this is achieved through host pattern recognition receptors that sense viral nucleic acid as foreign and initiate antiviral defenses through transcriptional upregulation of antiviral cytokines interferons (IFNs) and interferon stimulated genes (ISGs). However, aberrant production of IFN in the absence of viral infection leads to auto-inflammation and can be detrimental to the host. Here, we show that the DNA binding transcriptional repressor complex composed of Capicua (CIC) and Ataxin-1 like (ATXN1L) bind to 8-nucleotide motif near IFN and ISG promoters and block aberrant expression under homeostasis. However, during respiratory viral infections, this active repression is relieved by rapid degradation of the CIC-ATXN1L complex via the activation Mitogen‑activated protein kinase (MAPK) pathway, thereby priming the host cells ready to mount robust antiviral responses through canonical interferon regulatory factors (IRF), and signal transducer and activator of transcription (STAT) transcription factors. Importantly, murine Cic-Atxn1L also repress expression from IFN and ISGs promoters, demonstrating the conservation of this regulatory mechanism in murine species. Together, our studies define a new paradigm for regulation of IFN and ISGs through the evolutionarily conserved CIC-ATXN1L DNA binding transcription repressor complex under homeostasis and viral infection conditions.
2025-03-24 | GSE271899 | GEO