CDCA7 promotes TGF-β-induced epithelial-mesenchymal transition via transcriptionally regulating Smad4/Smad7 in ESCC
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA832795 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18957540_1.fastq.gz | Fastqsanger.gz | |||
| SRR18957540_2.fastq.gz | Fastqsanger.gz | |||
| SRR18957541_1.fastq.gz | Fastqsanger.gz | |||
| SRR18957541_2.fastq.gz | Fastqsanger.gz | |||
| SRR18957542_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose：Cell division cycle associated 7 (CDCA7) is a copy number amplification gene that contributes to the metastasis and invasion of tumors, including esophageal squamous cell carcinoma (ESCC). This present study aimed at clarifying whether high expression of CDCA7 promotes the metastasis and invasion of ESCC cell lines and exploring the underlying mechanisms implicated in EMT of ESCC. Mehtod：We established KYSE150 cell lines in which target gene has been knocked down by shRNA and KYSE180 cell lines in which target gene has been ovexpressed by plasmid.We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells.Each cell has three repetions. Result：KEGG pathway enrichment analysis on the data of RNA-seq showed that Wnt signaling pathway and TGF-β signaling pathway which are related to EMT process were screened out. Conclusion：CDCA7 was heavily involved in EMT by regulating the expression of Smad4 and Smad7 in TGF-β signaling pathway.
2023-01-11 | GSE201735 | GEO
Project description:Cell division cycle associated 7 (CDCA7) is a copy number amplification gene that contributes to the metastasis and invasion of tumors, including esophageal squamous cell carcinoma (ESCC). This present study aimed at clarifying whether high expression of CDCA7 promotes the metastasis and invasion of ESCC cell lines and exploring the underlying mechanisms implicated in epithelial-mesenchymal transition (EMT) of ESCC. The role of CDCA7 in the regulation of ESCC metastasis and invasion was evaluated using ESCC cell lines. Expression of EMT-related markers including E-cadherin, N-cadherin, Vimentin, Snail, and Slug, transforming growth factor β (TGF-β) signaling pathway including Smad2/3, p-Smad2/3, Smad4, and Smad7 were detected in CDCA7 knockdown and overexpressed cell lines. Dual-luciferase reporter assay and rescue assay were used to explore the underlying mechanisms that CDCA7 contributed to the metastasis and invasion of ESCC. High CDCA7 expression significantly promoted the metastasis and invasion of ESCC cell lines both in vivo and in vitro. Additionally, the expression of CDCA7 positively correlated with the expression of N-cadherin, Vimentin, Snail, Slug, TGF-β signaling pathway and negatively correlated with the expression of E-cadherin. Furthermore, CDCA7 transcriptionally regulated the expression of Smad4 and Smad7. Knockdown of CDCA7 inhibited the TGF-β signaling pathway and therefore inhibited EMT. Our data indicated that CDCA7 was heavily involved in EMT by regulating the expression of Smad4 and Smad7 in TGF-β signaling pathway. CDCA7 might be a new therapeutic target in the suppression of metastasis and invasion of ESCC.
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Project description:CDCA7, encoding a protein with a C-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of peri/centromeric satellite DNA. Previous work suggests that the CDCA7 CRD is implicated in DNA binding, which plays a key role in directing the DNA methylation mechinery to peri/centromeric regions. To identify potential genomic targets of CDCA7, we performed ChIP-Seq using CDCA7 knockout (KO) mouse embryonic stem cells (mESCs) stably expressing HA-tagged wild-type (WT) or ICF mutant (R285H) mCDCA7.
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Project description:Long-term management of inflammatory skin diseases is challenging because of side effects from repeated use of systemic treatments or topical corticosteroids. This study sought to identify novel mechanisms and developmental therapeutics for these diseases using genetic models and pharmacological approaches. We found mice overexpressing Smad7 in keratinocytes, but not mice overexpressing the N-terminal domain of Smad7 (N-Smad7), were resistant to imiquimod (IMQ)-induced Th1/17 and Th2 type inflammation. We generated a truncated Smad7 protein encompassing C-terminal Smad7 and PY motif fused with cell-penetrating Tat peptide (Tat-PYC-Smad7). Topically applied Tat-PYC-Smad7 to inflamed skin entered cells upon contact and attenuated IMQ-, 2,4-dinitrofluorobenzene-induced atopic dermatitis (AD) and tape-stripping inflammation (TS). RNAseq analyses of mouse skin exposed to these insults identified that in addition to inhibiting TGFβ/NFκB, Smad7 blunted IL22/STAT3 activation and associated pathogenesis, which is due to Smad7 transcriptionally upregulating IL22 antagonist IL22RA2. Mechanistically, Smad7 facilitated nuclear translocation and DNA binding of C/EBPβ to IL22RA2 promoter for IL22RA2 transactivation. Consistent to the above observations in mice, transcript levels of IL22RA2 were increased in human atopic dermatitis and psoriasis lesions with clinical remission. Our study identified the anti-inflammation functional domain of Smad7 and suggests mechanism and feasibility for developing Smad7-based biologics as a topical therapy for skin inflammatory disorders.
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Project description:Background & Aims: Although hepcidin expression was shown to be induced by the BMP signaling pathway, it is not yet known how iron regulates hepcidin and which of the BMP molecules is the endogenous regulator of iron homeostasis in vivo. We therefore assessed liver transcription profiles of mice fed an iron-deficient or an iron-enriched diet and looked for genes that were regulated similarly to hepcidin in that context. Methods: Genome-wide liver expression profiles of mice of the B6 and D2 genetic backgrounds subjected to iron-deficient, -balanced, or -enriched diets were obtained using Agilent Whole Genome microarrays. Real-time quantitative-PCR and western-blots were used to confirm microarray results and compare gene expression variations induced by secondary iron deficiency or iron overload with those consecutive to Smad4 or Hamp1-deficiency. Results: Among 1419 transcripts significantly modulated by the dietary iron content, four were regulated similarly to the hepcidin genes Hamp1 and Hamp2. They are coding for Bmp6, the regulator of Bmp/Smad signal transduction Smad7, the negative regulator of basic helix-loop-helix (bHLH) proteins Id1, and a protein with a bHLH domain, Atoh8. The iron overload developed by Smad4 and Hamp1-deficient mice also increased Bmp6 transcription. Body iron stores influence Smad1/5/8 phosphorylation and, as shown by analysis of mice with liver-specific disruption of Smad4, the binding partner for the receptor-activated Smads is necessary for activation of Smad7, Id1, and Atoh8 transcription by iron. Conclusions: Liver expression of Bmp6, Smad7, Id1, and Atoh8 is regulated by body iron stores and may participate in hepcidin regulation through the Bmp/Smad pathway. Keywords: response to dietary iron content
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Project description:Disruption of Cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that impacted large gene clusters. In brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3) and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.
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Project description:Disruption of Cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that impacted large gene clusters. In brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3) and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.
2024-02-09 | GSE211947 | GEO
Project description:Disruption of Cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that impacted large gene clusters. In brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3) and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.
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Project description:Disruption of Cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that impacted large gene clusters. In brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3) and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.
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Project description:Disruption of Cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that impacted large gene clusters. In brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3) and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.
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