Integrative multi‐omic analysis reveals neurodevelopmental gene dysregulation in <scp><i>CIC</i></scp>‐knockout and <scp><i>IDH1</i></scp>‐mutant cells

Lee, Stephen Dongsoo; Song, Jungeun; LeBlanc, Véronique G.; Marra, Marco A.

doi:10.1002/path.5835

Cited by 7 publications

(10 citation statements)

References 54 publications

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“…Binding of CIC to gene loci recruits histone deacetylases leading to transcriptional repression underpinning CIC function in development and tumorigenesis [ 63 ]. Targets of CIC regulation commonly identified in mammalian transcriptomic studies are the PEA3 sub-family of ETS transcription factors and DUSP Mapk phosphatases [ 40 , 64 – 66 ]. Interestingly, our transcriptomic analyses show that early expression of these genes does not significantly change in Cic knockdown embryos.…”

Section: Discussionmentioning

confidence: 99%

Regulation of gene expression downstream of a novel Fgf/Erk pathway during Xenopus development

Cowell,

King,

West

et al. 2023

PLoS ONE

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Activation of Map kinase/Erk signalling downstream of fibroblast growth factor (Fgf) tyrosine kinase receptors regulates gene expression required for mesoderm induction and patterning of the anteroposterior axis during Xenopus development. We have proposed that a subset of Fgf target genes are activated in the embyo in response to inhibition of a transcriptional repressor. Here we investigate the hypothesis that Cic (Capicua), which was originally identified as a transcriptional repressor negatively regulated by receptor tyrosine kinase/Erk signalling in Drosophila, is involved in regulating Fgf target gene expression in Xenopus. We characterise Xenopus Cic and show that it is widely expressed in the embryo. Fgf overexpression or ectodermal wounding, both of which potently activate Erk, reduce Cic protein levels in embryonic cells. In keeping with our hypothesis, we show that Cic knockdown and Fgf overexpression have overlapping effects on embryo development and gene expression. Transcriptomic analysis identifies a cohort of genes that are up-regulated by Fgf overexpression and Cic knockdown. We investigate two of these genes as putative targets of the proposed Fgf/Erk/Cic axis: fos and rasl11b, which encode a leucine zipper transcription factor and a ras family GTPase, respectively. We identify Cic consensus binding sites in a highly conserved region of intron 1 in the fos gene and Cic sites in the upstream regions of several other Fgf/Cic co-regulated genes, including rasl11b. We show that expression of fos and rasl11b is blocked in the early mesoderm when Fgf and Erk signalling is inhibited. In addition, we show that fos and rasl11b expression is associated with the Fgf independent activation of Erk at the site of ectodermal wounding. Our data support a role for a Fgf/Erk/Cic axis in regulating a subset of Fgf target genes during gastrulation and is suggestive that Erk signalling is involved in regulating Cic target genes at the site of ectodermal wounding.

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Section: Discussionmentioning

confidence: 99%

Regulation of gene expression downstream of a novel Fgf/Erk pathway during Xenopus development

Cowell,

King,

West

et al. 2023

PLoS ONE

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“…The 325 cohort and 693 cohort from the Chinese Glioma Genome Atlas (CGGA, http://www.cgga.org.cn/) were utilized for the validation of treatment response. Additionally, for validation purposes, we acquired data from 24 samples, including RNA-seq, DNA methylation-seq, and ChIP-seq, from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/, GEO accession: GSE121719, GSE121720, GSE121721, GSE189859, GSE189860, and GSE189857) 20,21 . Data for chromosomal three-dimensional structures (TADs) was retrieved from GSE77565 22 .…”

Section: Data Collection and Quality Controlmentioning

confidence: 99%

Integration of Multi-omics Data Revealed the Orphan CpG Islands and Enhancer-dominated Cis-regulatory Network in Glioma

yao,

Yao,

et al. 2024

Preprint

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Background: The complex transcriptional regulatory network leads to the poor prognosis of glioma. The role of orphan CpG islands (oCGIs) in the transcriptional regulatory network has been overlooked. Establishing a sophisticated transcriptional regulatory system is paramount.Methods: We constructed different cis-regulatory models through mutual information and Bayesian networks. We utilized eleven machine learning algorithms to develop classifiers that could effectively integrate multi-omics datasets. we utilized single-cell multi-omics data construct a higher-resolution cis-regulatory network. To investigate the binding interaction between oCGIs and transcription factors, we utilized chromatin immunoprecipitation assay and qRT-PCR. Furthermore, we assessed the proliferative status of various glioma subtypes using the MTT assay and immunohistochemistry.Results: The cis-regulatory network dominated by oCGIs and enhancers was significantly active in the glioma subtypes, mainly characterized by glioblastoma (Cluster 2). Direct regulation of target genes by oCGIs or enhancers is of great importance in the cis-regulatory network. Furthermore, based on single-cell multi-omics data, we found that the highly activated cis-regulatory network in Cluster 2 sustains the high proliferative potential of glioma cells. The upregulation of oCGIs and enhancers related genes in Cluster 2 results in glioma patients exhibiting resistance to radiotherapy and chemotherapy. These findings were further validated through glioma cell line related experiments.Conclusion: Our study systematically elucidated the cis-regulatory role of oCGIs for the first time. The comprehensive characterization of the multi-omics features of the oCGIs- and enhancers-dominated cis-regulatory network offers a novel insight into the pathogenesis of glioma and provides new strategies to treat this challenging disease.

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“…CIC ChIP-seq peaks for NHA cells were obtained from Lee et al [24] (Table S3 in that publication). ChIP-seq data from mouse embryonic stem cells (mESCs; fastq files) were downloaded from ArrayExpress (ERR2534130 [CIC ChIP] and ERR2534131 [IgG control], data from Weissmann et al [22]) and SRA (SRR7643337…”

Section: Chip-seq Analysismentioning

confidence: 99%

“…CIC is a transducer of receptor tyrosine kinase (RTK) signalling and functions through a default repression mechanism in which RTK activation leads to reduced CIC activity and subsequent de-repression of its target genes [19]. Targets of CIC are also themselves enriched for genes involved in the mitogen-activated protein kinase (MAPK) signalling cascade, including effectors (e.g., PTPN9, SHC3/4) and members of regulatory feedback mechanisms (e.g., DUSP4/5/6, SPRY2/4, SPRED1/2/3) [13,[20][21][22][23][24]. The cancer-promoting properties observed in cells with disrupted CIC activity have been explained, at least in part, by the de-repression of one or more of its known target genes that are effectors of MAPK signalling, especially the ETS transcription factors ETV1, ETV4, and ETV5 [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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

Takemon

LeBlanc

Song

et al. 2023

Cancers

Self Cite

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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.

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Integrative multi‐omic analysis reveals neurodevelopmental gene dysregulation in CIC‐knockout and IDH1‐mutant cells

Cited by 7 publications

References 54 publications

Regulation of gene expression downstream of a novel Fgf/Erk pathway during Xenopus development

Regulation of gene expression downstream of a novel Fgf/Erk pathway during Xenopus development

Integration of Multi-omics Data Revealed the Orphan CpG Islands and Enhancer-dominated Cis-regulatory Network in Glioma

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

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