Similar Datasets
Project description:Genomic interactions of Myc and rs55705857 in primary mouse derived neural stem cells
| PRJNA723203 | ENA
Project description:Mutations in ATP-dependent chromatin remodeler CHD8 cause one of the most frequent monogenetic forms of autism and also associate with brain overgrowth. Nevertheless, activities of CHD8 in autism-relevant cell types are still poorly understood. Here we purify the CHD8 protein from human neural stem cells and determine its interaction partners by mass spectrometry. We identify the TRRAP-complex, a coactivator of MYC and E2F transcription factors, as a prominent CHD8 interaction partner. CHD8 colocalizes genome-wide with TRRAP and TRRAP and CHD8 bind together to MYC- and E2F-target gene promoters in human neural stem cells. Acute depletion of CHD8 or TRRAP from human neural stem cells shows down-regulation of MYC- and E2F-target genes as most prominent gene-regulatory events. MYC and E2F factors are established oncogenes known to regulate cell growth. Our results link CHD8 to TRRAP in facilitating regulation of MYC- and E2F-target genes in neural stem cells.
2025-05-06 | PXD044582 | Pride
Project description:Long-range interactions of ribososomal DNA (rDNA) identified by 4C-seq in mouse wildtype, premalignant and malignant Eμ-Myc cells and tissue culture adapated Eμ-Myc-shUbtf and Eμ-Myc-LMP (empty vector) cells.
2019-02-06 | GSE70221 | GEO
Project description:The MYC oncogene encodes for the MYC protein and is frequently dysregulated across multiple cancer cell types, making it an attractive target for cancer therapy. MYC overexpression leads to MYC binding at active enhancers, resulting in a global transcriptional amplification of active genes. Since superenhancers are frequently dysregulated in cancer, we hypothesized that MYC preferentially invades into superenhancers and alters the cancer genome organization. To that end, we performed ChIP-seq, RNA-seq, 4C-seq and SIQHiC (Spike-in Quantitative Hi-C) on the U2OS osteosarcoma cell line with tetracycline-inducible MYC. MYC overexpression in U2OS cells modulated histone acetylation and increased MYC binding at superenhancers. SIQHiC analysis revealed increased global chromatin contact frequency, particularly at chromatin interactions connecting MYC binding sites at promoters and enhancers. Immunofluorescence staining showed that MYC molecules formed punctate foci at these transcriptionally active domains after MYC overexpression. These results demonstrate the accumulation of overexpressed MYC at promoter-enhancer hubs and suggest that MYC invades into enhancers through spatial proximity. At the same time, the increased protein-protein interactions may strengthen these chromatin interactions to increase chromatin contact frequency. CTCF siRNA knockdown in MYC overexpressed U2OS cells demonstrated that removal of architectural proteins can disperse MYC and abrogate the increase in chromatin contacts. By elucidating the chromatin landscape of MYC driven cancers, we can potentially target MYC associated chromatin interactions for cancer therapy.
2022-01-17 | GSE164777 | GEO
Project description:Vision depends on the functional interplay between the photoreceptor cells of the neural retina and the supporting cells of the underlying retinal pigment epithelium (RPE). Many genes involved in inherited retinal diseases (IRD) display highly specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis-regulatory elements (CREs) in 3D nuclear space. To understand the role of differential chromatin architecture in establishing tissue-specific expression patterns at IRD loci in the human neural retina and the RPE, we mapped genome-wide chromatin interactions by applying in situ Hi-C and H3K4me3 HiChIP to human adult post-mortem donor retinas. A comparative 3D genome analysis between neural retina and RPE revealed that almost 60% of known IRD genes were marked by differential cis-regulatory interactions or 3D genome structure. Furthermore, we zoomed in on tissue-specific chromatin interactions at the ABCA4 locus, which is implicated in the most common autosomal recessive IRD. We constructed high-resolution ABCA4 interaction profiles using UMI-4C, which, upon integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish, revealed tissue-specific CREs for ABCA4. In summary, through extensive comparative 3D genome mapping, based on genome-wide (Hi-C), promoter-centric (HiChIP) and locus-specific (UMI-4C) assays of human neural retina and RPE, we have shown that gene regulation at key IRD loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for genomic variation underlying unsolved IRD.
2024-04-08 | GSE236021 | GEO
Project description:Vision depends on the functional interplay between the photoreceptor cells of the neural retina and the supporting cells of the underlying retinal pigment epithelium (RPE). Many genes involved in inherited retinal diseases (IRD) display highly specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis-regulatory elements (CREs) in 3D nuclear space. To understand the role of differential chromatin architecture in establishing tissue-specific expression patterns at IRD loci in the human neural retina and the RPE, we mapped genome-wide chromatin interactions by applying in situ Hi-C and H3K4me3 HiChIP to human adult post-mortem donor retinas. A comparative 3D genome analysis between neural retina and RPE revealed that almost 60% of known IRD genes were marked by differential cis-regulatory interactions or 3D genome structure. Furthermore, we zoomed in on tissue-specific chromatin interactions at the ABCA4 locus, which is implicated in the most common autosomal recessive IRD. We constructed high-resolution ABCA4 interaction profiles using UMI-4C, which, upon integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish, revealed tissue-specific CREs for ABCA4. In summary, through extensive comparative 3D genome mapping, based on genome-wide (Hi-C), promoter-centric (HiChIP) and locus-specific (UMI-4C) assays of human neural retina and RPE, we have shown that gene regulation at key IRD loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for genomic variation underlying unsolved IRD.
2024-04-08 | GSE235728 | GEO
Project description:Vision depends on the functional interplay between the photoreceptor cells of the neural retina and the supporting cells of the underlying retinal pigment epithelium (RPE). Many genes involved in inherited retinal diseases (IRD) display highly specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis-regulatory elements (CREs) in 3D nuclear space. To understand the role of differential chromatin architecture in establishing tissue-specific expression patterns at IRD loci in the human neural retina and the RPE, we mapped genome-wide chromatin interactions by applying in situ Hi-C and H3K4me3 HiChIP to human adult post-mortem donor retinas. A comparative 3D genome analysis between neural retina and RPE revealed that almost 60% of known IRD genes were marked by differential cis-regulatory interactions or 3D genome structure. Furthermore, we zoomed in on tissue-specific chromatin interactions at the ABCA4 locus, which is implicated in the most common autosomal recessive IRD. We constructed high-resolution ABCA4 interaction profiles using UMI-4C, which, upon integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish, revealed tissue-specific CREs for ABCA4. In summary, through extensive comparative 3D genome mapping, based on genome-wide (Hi-C), promoter-centric (HiChIP) and locus-specific (UMI-4C) assays of human neural retina and RPE, we have shown that gene regulation at key IRD loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for genomic variation underlying unsolved IRD.
2024-04-08 | GSE235726 | GEO
Project description:Deletion and duplication of the 16p11.2 genomic locus are associated with opposing changes in brain size. To determine cellular mechanisms that might underlie these opposing phenotypes, we performed quantitative phosphoproteomics on induced pluripotent stem cells (iPSC) derived neural progenitor cells (NPCs) obtained from unaffected individuals, 16p11.2 deletion, and duplication carriers. Differentially phosphorylated proteins were enriched in centrosomal and cilia proteins. Deletion NPCs showed longer primary cilium compared to unaffected individuals, while stunted cilia were observed in duplication NPCs. Through cellular screens in NPCs, we determined the contribution of genes within the 16p11.2 locus to cilium length. TAOK2 and PPP4C were found to regulate primary cilia length. NPCs lacking TAOK2, a protein kinase, exhibited elongated cilia, aberrant IFT88 and pericentrin accumulation, and impaired SHH signaling. These findings implicate aberrant cilia length in the pathophysiology of 16p11.2 copy number variation, and establish TAOK2 kinase as a regulator of primary cilium length.
2025-07-28 | PXD066614 | Pride
Project description:The numerous neurons and glia that form the brain originate from tightly controlled growth and division of neural stem cells, regulated systemically by known extrinsic signals. However, the intrinsic mechanisms that control the characteristic proliferation rates of individual neural stem cells are unknown. Here, we show that the size and division rates of Drosophila neural stem cells (neuroblasts) are controlled by the highly conserved RNA binding protein Imp (IGF2BP), via one of its top binding targets in the brain, myc mRNA. We show that Imp stabilises myc mRNA leading to increased Myc protein levels, larger neuroblasts, and faster division rates. Declining Imp levels throughout development limit myc mRNA stability to restrain neuroblast growth and division, while heterogeneous Imp expression correlates with myc mRNA stability between individual neuroblasts in the brain. We propose that Imp-dependent regulation of myc mRNA stability fine-tunes individual neural stem cell proliferation rates.
2020-02-05 | GSE140704 | GEO