Gene expression profiles in naïve and activated CD4+ T cells from WT and Capicua (Cic)-deficient mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE84125 | GEO | 2017/05/22
REPOSITORIES: GEO
Similar Datasets
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
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.
2024-06-06 | GSE269295 | GEO
Project description:Purpose : The goal of this study is to compare the repertoire of T cell receptor (TCR) alpha and beta chain between WT and CIC-deficient thymic CD4+ single positive (SP) T cells, in both non-Treg and Treg populations, to confirm the effect of CIC deficiency on T cell development in the aspect of TCR repertoire. Methods : Treg (CD4+CD8-CD25+GFP+) and non-Treg (CD4+CD8-GFP-) cells from Foxp3-GFP;Cicf/f and Foxp3-GFP;Cicf/f;Vav1-Cre mice were sorted by MoFlo-XDP (Beckman Coulter). Total RNA was extracted using RiboEX (GeneAll) according to the manufacturer's instructions. RNA was then amplified using a commercially available multiplex primer mix covering the TCR alpha and beta chains in two separate PCR reactions. Reverse transcription and subsequent PCR amplification (RT-PCR1) were performed using the Qiagen OneStep RT PCR mix (Qiagen). The cDNA was selected and unused primers were removed by SPRIselect bead selection (Beckman Coulter) followed by a second round of amplification performed with a pair of primers specific for communal sites engineered onto the 5ʹ end of the C- and V- primers used during RT-PCR1. After library preparation, paired-end sequencing was performed using the Illumina Miseq v3 600-cycle Reagent Kit (Illumina). Results : We observed increased frequency of TCRs with long CDR3 length in CIC-deficient non-Treg and Treg cells. We also found significant alterations in the TCR repertoire of TCR beta chain in CIC-deficient Treg cells compared to WT cells, including altered frequency of V and J chain usage. Conclusions : Our study represents the first comparative analysis of TCR repertoire of thymic CD4 SP cells from WT and hematopoietic lineage cell-specific Cic deficient mice. We concluded that CIC deficiency leads to alterations in TCR repertoire of thymic Treg cells.
2021-05-07 | GSE173996 | GEO
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
Project description:Purpose : The goal of this study is to compare the gene expression profiles between wild-type (WT) and CIC-deficient DP thymocytes to understand the molecular mechanisms of CIC regulation of T cell development, especially in DP thymocytes. Methods : DP thymocytes (lin-CD4+CD8+TCRlo (Lineage : CD11b, CD11c, CD19, NK1.1, Gr-1, γδTCR, and TER119)) from thymus were sorted by a MoFlo-XDP (Beckman Coulter). Total RNA was extracted using RiboEX (GeneAll) according to the manufacturer's instructions. The library for mRNA sequencing was generated using the TruSeq Stranded Total RNA LT Sample Prep Kit (Illumina) and sequencing was performed with NovaSeq 6000 (Illumina). Results : Trimmed reads were mapped to the mouse reference genome (mm10 RefSeq) with HISAT2, and the transcripts were assembled using StringTie. A total of 482 differentially expressed genes (DEGs; fold change > 2 and P-value < 0.05) were generated using edgeR. The 263 upregulated genes included known CIC target genes such as Etv1, Etv4, Etv5, Spry4, Spred1, Dusp4, and Dusp6. Conclusions : Our study represents the first comparative analysis of DP thymocytes from WT and hematopoietic lineage cell-specific Cic deficient mice. We concluded that CIC deficiency leads to impaired positive and negative selection, and TCR signaling in DP cells. The attenuation of TCR signaling is caused by derepression of CIC target genes involved in dephosphorylation of ERK.
2021-05-06 | GSE173909 | GEO
Project description:CIC is a HMG box-containing transcriptional repressor evolutionarily conserved from C. elegans to human. It's known to associate with various types of cancer but physiological function of CIC remain largely unknown. In this study, we characterized Cic hypomorphic (Cic-L-/-) mice and identified critical roles for of CIC in drug metabolism and bile acid homeostasis. Total RNA obtained from isolated liver tissue of Cic-L-/- mouse compared to liver tissue of normal mouse
2015-04-15 | E-GEOD-60375 | biostudies-arrayexpress
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
Project description:CIC is a HMG box-containing transcriptional repressor evolutionarily conserved from C. elegans to human. It's known to associate with various types of cancer but physiological function of CIC remain largely unknown. In this study, we characterized Cic hypomorphic (Cic-L-/-) mice and identified critical roles for of CIC in drug metabolism and bile acid homeostasis.
2015-04-15 | GSE60375 | GEO
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
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.
2011-11-07 | GSE32051 | GEO