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First Generation Tools for the Modeling of Capicua-Family Fusion Oncoprotein-Driven Cancers (May 2024 Dataset)

ABSTRACT: The rearrangement of separate genes into neomorphic fusion oncogenes can occur after chromosomal damage and repair, causing cancer. In the case of sarcomas, several tumor types are driven by fusion oncogenes comprised of various partner genes. We study fusions involving capicua (CIC), a developmental transcriptional repressor whose fusion to 3' partner genes including DUX4, NUTM1, and LEUTX drives devastating tumors of the soft tissue, central nervous system, and spine. Here we develop the first tools to investigate previously understudied fusions of CIC and ATXN1 and express them in 293T cells to uncover convergent/divergent biology between various CIC-family fusions depending on what the specific partner genes are.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295623 | GEO | 2025/05/13

REPOSITORIES: GEO

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First Generation Tools for the Modeling of Capicua-Family Fusion Oncoprotein-Driven Cancers (February 2025 Dataset)

Project description:The rearrangement of separate genes into neomorphic fusion oncogenes can occur after chromosomal damage and repair, causing cancer. In the case of sarcomas, several tumor types are driven by fusion oncogenes comprised of various partner genes. We study fusions involving capicua (CIC), a developmental transcriptional repressor whose fusion to 3' partner genes including DUX4, NUTM1, and LEUTX drives devastating tumors of the soft tissue, central nervous system, and spine. Here we develop the first tools to investigate previously understudied fusions of CIC and ATXN1 and express them in 293T cells to uncover convergent/divergent biology between various CIC-family fusions depending on what the specific partner genes are.

2025-05-13 | GSE295625 | GEO

First Generation Tools for the Modeling of Capicua-Family Fusion Oncoprotein-Driven Cancers (April 2023 Dataset)

2025-05-13 | GSE295624 | GEO

The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein.

Project description:Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.

2024-10-16 | GSE279546 | GEO

The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein

2024-06-06 | GSE269295 | GEO

Capicua-dependent transcriptional changes in adult mouse cerebellum

Project description:Analysis of cerebella from Capicua (Cic) mutant mice and wild-type controls at 28 days of age (P28). Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by expansion of a translated CAG repeat in Ataxin-1 (ATXN1). The transcriptional repressor Cic binds directly to Atxn1 and plays a key role in SCA1 pathogenesis. Two isoforms of Cic, long (Cic-L) and short (Cic-S), are transcribed from alternative promoters. Using embryonic stem cells in which the Cic locus was targeted by an insertion of a genetrap cassette between exon 1 of the Cic-L isoform and exon 1 of the Cic-S isoform, we generated mice that carried this allele and backcrossed these onto a Swiss Webster (CD-1) strain for >6 generations. The resulting Cic-L-/- mice completely lack the Cic-L isoform with ~10% of Cic-S remaining. These data were used to compare with previous microarray data to determine the Cic-depedent pathogenic mechanisms in SCA1. Total RNA from cerebella of wild-type (n=4) and Capicua mutant mice (n=4) at 28 days of age was prepared and labeled according the manufacturer's protocols for the Affymetrix Mouse Gene 1.0 ST Array.

2011-11-07 | E-GEOD-32051 | biostudies-arrayexpress

Capicua-dependent transcriptional changes in adult mouse cerebellum

2011-11-07 | GSE32051 | GEO

Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature

Project description:Pediatric neoplasms in the central nervous system show an extensive clinical and molecular heterogeneity. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Unsupervised visualization of genome-wide DNA methylation array data revealed a molecularly distinct type of pediatric high-grade neuroepithelial tumor with fusions involving the capicua transcriptional repressor (CIC) gene, with the most common fusion being CIC::LEUTX. Histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC.

2023-03-10 | GSE223546 | GEO

Binding of the Capicua repressor in response to pulses of ERK signaling in the early Drosophila embryo

Project description:We have measured by ChIP-seq the binding of Capicua transcriptional repressor (Cic) in Drosophila melanogaster embryos at early nuclear cycle 14. We compared binding in response to ERK activation, utilizing optogenetics.

2020-03-05 | GSE130584 | GEO

Capicua controls Toll/IL-1 signaling targets independently of RTK regulation

Project description:The HMG-box protein Capicua (Cic) is a conserved transcriptional repressor that functions downstream of receptor tyrosine kinase (RTK) signaling pathways in a relatively simple switch: in the absence of signaling, Cic represses RTK-responsive genes by binding to nearly invariant sites in DNA, whereas activation of RTK signaling downregulates Cic activity, leading to derepression of its targets. This mechanism controls gene expression in both Drosophila and mammals, but whether Cic can also function via other regulatory mechanisms remains unknown. Here we characterize an RTK-independent role of Cic in regulating spatially restricted expression of Toll/IL-1 signaling targets in Drosophila embryogenesis. We show that Cic represses those targets by binding to suboptimal DNA sites of lower affinity than its known consensus sites. This binding depends on Dorsal/NF-kB, which translocates into the nucleus upon Toll activation and binds next to the Cic sites. As a result, Cic binds to and represses Toll targets only in regions with nuclear Dorsal. These results reveal a new mode of Cic regulation unrelated to the well-established RTK-Cic depression axis and implicate cooperative binding in conjunction with low-affinity binding sites as an important mechanism of enhancer regulation. Given that Cic plays a role in many developmental and pathological processes in mammals, our results raise the possibility that some of these Cic functions are independent of RTK regulation and may depend on cofactor-assisted DNA binding.

2018-01-05 | GSE104839 | GEO

ATXN1-NUTM1 may define a new brain tumor entity and expand the histologic spectrum of NUTM1-rearranged neoplasia

Project description:An ATXN1-NUTM1 brain tumor entity

2019-10-09 | GSE138550 | GEO