The C-terminal 4CXXC-type zinc finger domain of CDCA7 recognizes hemimethylated DNA and modulates activities of chromatin remodeling enzyme HELLS
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ABSTRACT:
PROVIDER: PRJNA1125447 | ENA |
REPOSITORIES: ENA
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Project description:The chromatin-remodeling enzyme helicase lymphoid-specific (HELLS) interacts with cell division cycle-associated 7 (CDCA7) on nucleosomes and is involved in the regulation of DNA methylation in higher organisms. Mutations in these genes cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, which also results in DNA hypomethylation of satellite repeat regions. We investigated the functional domains of human CDCA7 in HELLS using several mutant CDCA7 proteins. The central region is critical for binding to HELLS, activation of ATPase, and nucleosome sliding activities of HELLS-CDCA7. The N-terminal region tends to inhibit ATPase activity. The C-terminal 4CXXC-type zinc finger domain contributes to CpG and hemimethylated CpG DNA preference for DNA-dependent HELLS-CDCA7 ATPase activity. Furthermore, CDCA7 showed a binding preference to DNA containing hemimethylated CpG, and replication-dependent pericentromeric heterochromatin foci formation of CDCA7 with HELLS was observed in mouse embryonic stem cells; however, all these phenotypes were lost in the case of an ICF syndrome mutant of CDCA7 mutated in the zinc finger domain. Thus, CDCA7 most likely plays a role in the recruitment of HELLS, activates its chromatin remodeling function, and efficiently induces DNA methylation, especially at hemimethylated replication sites.
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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:The activating E2F-transcription factors are best known for their dependence on the Retinoblastoma protein and their role in cellular proliferation. E2F3 is uniquely amplified in specific human tumours where its expression is inversely correlated with the survival of patients. Here, E2F3 interaction partners were identified by mass spectrometric analysis. We show that the SNF2-like HELLS interacts with E2F3 in vivo and cooperates with its oncogenic functions. Depletion of HELLS severely perturbs the induction of E2F-target genes, hinders cell cycle re-entry and growth. Using chromatin immmunoprecipitation coupled to sequencing we identified genome-wide targets of HELLS and E2F3. Our analysis revealed that HELLS binds near promoters of active genes, including the trithorax-related MLL1, and co-regulates E2F3-dependent genes. Our analysis is the first to link HELLS with E2F-controlled processes that are critical to establish a proliferative tumour circuitry. Strikingly, just as E2F3, HELLS is overexpressed in human tumours including prostate cancer, indicating that either factor may contribute to the malignant progression of tumours. Our work reveals that HELLS is important for E2F3 in tumour cell proliferation.
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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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Project description:We used novel genetically engineered mouse models to investigate the role of HELLS during tumorigenesis. Loss of HELLS drastically decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Tumors from Rb1/p107 DKO and Rb1/p107/Hells TKO mice were analyzed for gene expression using RNA-seq.
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Project description:The activating E2F-transcription factors are best known for their dependence on the Retinoblastoma protein and their role in cellular proliferation. E2F3 is uniquely amplified in specific human tumours where its expression is inversely correlated with the survival of patients. Here, E2F3 interaction partners were identified by mass spectrometric analysis. We show that the SNF2-like HELLS interacts with E2F3 in vivo and cooperates with its oncogenic functions. Depletion of HELLS severely perturbs the induction of E2F-target genes, hinders cell cycle re-entry and growth. Using chromatin immmunoprecipitation coupled to sequencing we identified genome-wide targets of HELLS and E2F3. Our analysis revealed that HELLS binds near promoters of active genes, including the trithorax-related MLL1, and co-regulates E2F3-dependent genes. Our analysis is the first to link HELLS with E2F-controlled processes that are critical to establish a proliferative tumour circuitry. Strikingly, just as E2F3, HELLS is overexpressed in human tumours including prostate cancer, indicating that either factor may contribute to the malignant progression of tumours. Our work reveals that HELLS is important for E2F3 in tumour cell proliferation. Examination of E2F3, Hells, and H3K27me3 in 2 cell types.
2011-12-19 | E-GEOD-33791 | biostudies-arrayexpress
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 | GSE211950 | 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:We used novel genetically engineered mouse models to investigate the role of HELLS during tumorigenesis. Loss of HELLS drastically decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Retinae from Rb1/p107 DKO and Rb1/p107/Hells TKO mice at postnatal day 21 were analyzed for gene expression using RNA-seq.
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