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Multi-Omic Analysis of CIC’s Functional Networks Reveals Novel Interaction Partners and a Potential Role in Mitotic Fidelity

ABSTRACT: CIC encodes a transcriptional repressor and MAPK signalling effector that is inactivated by loss-of-function mutations in several cancer types, consistent with a role as a tumour suppressor. Here, we used bioinformatic, genomic, and proteomic approaches to investigate CIC’s interaction networks. We observed both previously identified and novel candidate interactions between CIC and SWI/SNF complex members, as well as novel interactions between CIC and cell cycle regulators and RNA processing factors. We found that CIC loss is associated with an increased frequency of mitotic defects in human cell lines and an in vivo mouse model and with dysregulated expression of mitotic regulators. We also observed aberrant splicing in CIC-deficient cell lines, predominantly at 3′ and 5′ untranslated regions of genes, including genes involved in MAPK signalling, DNA repair, and cell cycle regulation. Our study thus characterises the complexity of CIC’s functional network and describes the effect of its loss on cell cycle regulation, mitotic integrity, and transcriptional splicing, thereby expanding our understanding of CIC’s potential roles in cancer. In addition, our work exemplifies how multi-omic, network-based analyses can be used to uncover novel insights into the interconnected functions of pleiotropic genes/proteins across cellular contexts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193765 | GEO | 2023/06/29

REPOSITORIES: GEO

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Multi-omic analyses reveal interaction networks linking CIC to cell cycle regulation

Project description:CIC encodes a transcriptional repressor inactivated by loss-of-function mutations in several cancer types, indicating that it may function as a tumor suppressor. Recent data indicate that CIC may regulate cell cycle genes in humans; however, a thorough investigation of this proposed role has not yet been reported. Here, we used single-cell RNA sequencing technology to provide evidence that inactivation of CIC in human cell lines resulted in transcriptional dysregulation of genes involved in cell cycle control. We also mapped CIC’s protein-protein and genetic interaction networks, identifying interactions between CIC and members of the Switch/Sucrose Non-Fermenting (SWI/SNF) complex, as well as novel candidate interactions between CIC and cell cycle regulators. We further showed that CIC loss was associated with an increased frequency of mitotic defects in human cell lines and a mouse model. Overall, our study positions CIC as a cell cycle regulator and indicates that CIC loss can lead to mitotic errors, consistent with CIC’s emerging role as a tumor suppressor of relevance in several cancer contexts.

2023-06-30 | PXD030942 | Pride

RNA-seq of Glioma Neural Stem (GNS) cell line G144 after MEK inhibition in wild type (WT) and CIC (Capicua) depleted cells.

Project description:We identified genome-wide binding patterns of CIC in several different cell types and find that CIC target genes are enriched for MAPK effector genes involved in cell cycle regulation and proliferation. CIC binding to its target genes is abolished by high MAPK activity, which leads to hyperacetylation and their transcriptional activation. Inhibition of MAPK signaling via MEK inhibition leads to recruitment of CIC to its target genes. ChIP-seq data of G144 cells after MEK inhibition and CIC knockout is available under accession E-MTAB-6682

2018-05-31 | E-MTAB-6681 | biostudies-arrayexpress

ChIP-seq of CIC (Capicua) and histone marks (H3K9ac, H3K27ac and H3K4me1) in glioma neural stem cells (GNS) G144, human foetal neural stem cells (hNSC) and mouse embryonic stem cells (mESC),

Project description:We identified genome-wide binding patterns of CIC in several different cell types and find that CIC target genes are enriched for MAPK effector genes involved in cell cycle regulation and proliferation. CIC binding to its target genes is abolished by high MAPK activity, which leads to hyperacetylation and their transcriptional activation. Inhibition of MAPK signaling via MEK inhibition leads to recruitment of CIC to its target genes. Expression data of G144 cells after MEK inhibition and CIC knockout is available under accession E-MTAB-6681

2018-05-31 | E-MTAB-6682 | biostudies-arrayexpress

Transcriptomic and Epigenomic Profiles of CIC-knockout and IDH1 mutant cells [WGBS]

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

Transcriptomic and Epigenomic Profiles of CIC-knockout and IDH1 mutant cells [RNA-seq]

2021-12-01 | GSE189859 | GEO

Transcriptomic and Epigenomic Profiles of CIC-knockout and IDH1 mutant cells [cic_chip]

2021-12-01 | GSE189858 | GEO

Transcriptomic and Epigenomic Profiles of CIC-knockout and IDH1 mutant cells [histone_chip]

2021-12-01 | GSE189857 | GEO

Transcriptomic analysis of CIC and ATXN1L in normal human astrocytes

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

Capicua-dependent transcriptional changes in human cancer cell lines treated with trametinib

Project description:We performed a genome-scale CRISPR screen in a KRAS-mutant pancreatic cancer cell line treated with the MEK inhibitor trametinib, and found that loss of the transcriptional repressor CIC confers resistance to MEK inhibition. We determined that CIC loss also confers resistance to MEK or BRAF inhibition in lung cancer, colorectal cancer, and melanoma cell lines with mutant RAS or BRAF. CIC is a transcriptional repressor that is phosphorylated and inhibited by the MAPK pathway. We hypothesized that inhibition of the MAPK pathway would lead to activation of CIC and repression of CIC target genes. Loss of CIC would therefore restore expression of these genes, conferring drug resistance. To identify the relevant CIC target genes that mediate trametinib resistace, we generated 4 Cas9-expressing cell lines from different lineages and with different RAS or RAF mutations, and generated control (gGFP) or CIC-knockout (gCIC) cell lines. We treated cells with DMSO or trametinib for 24 hours, and performed NRA-seq. We found that trametinib treatment reduces expression of at least one member of the PEA3 family of ETS transcription factors (ETV1, ETV4, and ETV5) in all cell lines assessed, and that loss of CIC results in maintained expression of these genes despite MEK inhibition. We further validated that ETV1, 4, and 5 expression was necessary for resistance mediated by CIC loss; and that ETV1, 4, or 5 expression was sufficient to confer trametinib resistance.

2017-05-31 | GSE78519 | GEO

Expression data from CIC wild type and knockout cell lines

Project description:Type I low-grade gliomas (LGGs), characterized by 1p/19q co-deletions and IDH1/2 mutations, show superior overall survival compared to other gliomas. Approximately 70% of cases harbour mutations in the Capicua (CIC) gene, whose product is a transcriptional repressor whose transcriptional network has yet to be extensively studied in human cells. To address this, we developed CIC knockout cell lines and used transcriptome analyses to study the consequences of CIC loss. Results were further compared to data for Type I LGGs and stomach adenocarcinomas from The Cancer Genome Atlas (TCGA). We find that CIC appears to regulate the expression of genes involved in cell-cell adhesion and nervous system development. CIC deficiency is also found to be associated with a MEK activation transcriptional signature and to act as an effector of MEK signalling. Loss of CIC may thus present a novel mechanism for the dysregulation of this and other oncogenic pathways.

2017-04-15 | GSE80359 | GEO

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