Re-Wiring 3D Nuclear Architecture by a Single Transcription Factor during Somatic Cell Reprogramming
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA385345 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-09-10 | GSE98530 | GEO
Project description: Not available
| S-EPMC6842445 | biostudies-literature
Project description:Crosstalk and complexity within signaling pathways has limited our ability to devise rational strategies for using network biology to treat human disease. This is particularly problematic in cancer where oncogenes that drive or maintain the tumorigenic state alter the normal flow of molecular information within signaling networks that control growth, survival and death. Understanding the architecture of oncogenic signaling pathways, and how these networks are re-wired by ligands or drugs, could provide opportunities for the specific targeting of oncogene-driven tumors. Here we use a systems biology-based approach to explore synergistic therapeutic strategies to optimize the killing of triple negative breast cancer cells, an incompletely understood tumor type with a poor treatment outcome. Using targeted inhibition of oncogenic signaling pathways combined with DNA damaging chemotherapy, we report the surprising finding that time-staggered EGFR inhibition, but not simultaneous co-administration, can dramatically sensitize the apoptotic response of a subset of triple-negative cells to conventional DNA damaging agents. A systematic analysis of the order and timing of inhibitor/genotoxin presentation—using a combination of high-density time-dependent activity measurements of signaling networks, gene expression profiles, cell phenotypic responses, and mathematical modeling—revealed an approach for altering the intrinsic oncogenic state of the cell through dynamic re-wiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death, through re-activation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state. Three or 4 replicates of 3 different cell lines at time points 0minutes, 30minutes, 6 hours and 1 day after EGFR inhibition with erlotinib
2012-05-14 | E-GEOD-30516 | biostudies-arrayexpress
Project description:Comparative 3D Genome Architecture in Vertebrates
| PRJNA704983 | ENA
Project description:Crosstalk and complexity within signaling pathways has limited our ability to devise rational strategies for using network biology to treat human disease. This is particularly problematic in cancer where oncogenes that drive or maintain the tumorigenic state alter the normal flow of molecular information within signaling networks that control growth, survival and death. Understanding the architecture of oncogenic signaling pathways, and how these networks are re-wired by ligands or drugs, could provide opportunities for the specific targeting of oncogene-driven tumors. Here we use a systems biology-based approach to explore synergistic therapeutic strategies to optimize the killing of triple negative breast cancer cells, an incompletely understood tumor type with a poor treatment outcome. Using targeted inhibition of oncogenic signaling pathways combined with DNA damaging chemotherapy, we report the surprising finding that time-staggered EGFR inhibition, but not simultaneous co-administration, can dramatically sensitize the apoptotic response of a subset of triple-negative cells to conventional DNA damaging agents. A systematic analysis of the order and timing of inhibitor/genotoxin presentation—using a combination of high-density time-dependent activity measurements of signaling networks, gene expression profiles, cell phenotypic responses, and mathematical modeling—revealed an approach for altering the intrinsic oncogenic state of the cell through dynamic re-wiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death, through re-activation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.
2012-05-15 | GSE30516 | GEO
Project description:Background: Epithelial-stromal crosstalk plays a critical role in invasive breast cancer (IBC) pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. Results: We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive re-wiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, ER-positive IBC, and ER-negative IBC, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in IBC mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas. Conclusions: Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially-localized transcriptomic data. The analysis provides new biological insights into the re-wiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer. 36 flash-frozen human primary breast cancer samples were subjected to laser capture microdissection to separately isolate matched tumor epithelial and tumor-associated stromal components. RNA was isolated, subjected to 2 rounds of amplification, and hybridized on Agilent 4x44K microarrays along with a common reference (single round-amplified commercially obtained Universal Human Reference RNA) in a dyeswap design. For two samples of tumor-associated stroma, a second technical replicate was performed. Samples were labelled as ER-positive based on ESR1 gene expression levels in the tumor epithelium, using univariate Gaussian mixture model-based clustering via the mclust package in R.
2015-05-12 | E-GEOD-68744 | biostudies-arrayexpress
Project description:The oocyte cytoplasm can reprogram somatic cell nucleus into a totipotent state but with low efficiency. The spatiotemporal chromatin organization of somatic cell nuclear transfer (SCNT) embryos remains elusive. Here, we examined higher-order chromatin structures of mouse SCNT embryos using an optimized low-input Hi-C approach. We found that the donor cell chromatin transformed to metaphase state rapidly after injection along with the dissolution of typical 3D chromatin structures. Intriguingly, the donor cell genome underwent a transition from mitotic metaphase-like state to meiosis metaphase II-like state within one hour after activation. Subsequently, weak chromatin compartments and topologically associating domains (TADs) emerged at 6 hours after activation. Then TADs were gradually removed until the 2-cell stage and then progressively reestablished. We found that relative few distal (> 2 Mb) interactions were present in 2-cell stage SCNT embryos. Also, obvious differences in compartment and TAD organization between fertilization-derived and SCNT embryos were observed in early stages (2-8 cell stages). Many interactions between super-enhancers and promoters were not successfully established in SCNT embryos, and these interactions were further shown important for zygotic genome activation (ZGA). Moreover, we demonstrate that the aberrant chromatin architecture reorganization in SCNT embryos may be due to the persistent H3K9me3 and can be partially rescued by the Kdm4d overexpression. This study therefore provides novel insight into chromatin architecture reorganization during SCNT embryo development.
2020-02-27 | GSE146001 | GEO
Project description:Three-dimensional genome architecture influences the regulation of essential nuclear processes, such as gene transcription. However, how 3D genome architecture is affected by evolutionary forces within major lineages remains unclear. Here, we report a comprehensive comparison of 3D genomes, using high resolution Hi-C data in fibroblast cells of fish, chickens, and 10 mammalian species. This analysis shows a correlation between genome size and chromosome length that affects chromosomal territory (CT) organization in the upper hierarchy of genome architecture, whereas lower hierarchical features, including local transcriptional availability of DNA, are selected through vertebrate’s evolution. Further, conservation of topologically associating domains (TADs) appears strongly associated with the modularity of expression profiles across species. Additionally, LINE and SINE transposable elements likely contribute to heterochromatin and euchromatin organization, respectively, during the evolution of genome architecture. These findings can guide ongoing investigations of genome evolution by extending our understanding of the mechanisms shaping genome architecture.
2022-04-12 | GSE167580 | GEO
Project description:Three-dimensional genome architecture influences the regulation of essential nuclear processes, such as gene transcription. However, how 3D genome architecture is affected by evolutionary forces within major lineages remains unclear. Here, we report a comprehensive comparison of 3D genomes, using high resolution Hi-C data in fibroblast cells of fish, chickens, and 10 mammalian species. This analysis shows a correlation between genome size and chromosome length that affects chromosomal territory (CT) organization in the upper hierarchy of genome architecture, whereas lower hierarchical features, including local transcriptional availability of DNA, are selected through vertebrate’s evolution. Further, conservation of topologically associating domains (TADs) appears strongly associated with the modularity of expression profiles across species. Additionally, LINE and SINE transposable elements likely contribute to heterochromatin and euchromatin organization, respectively, during the evolution of genome architecture. These findings can guide ongoing investigations of genome evolution by extending our understanding of the mechanisms shaping genome architecture.
2022-04-12 | GSE167579 | GEO
Project description:Higher-order chromatin conformation plays critical role in regulating gene expression and biological development, here we show that HNRNPU, a nuclear matrix attachment factor, is a regulator of 3D genome architecture at multiple levels in mouse hepatocytes. We demonstrate that depletion of HNRNPU results into a global reorganization of nuclear bodies and re-localization of chromatin towards nuclear periphery. Additionally, upon HNRNPU depletion, chromatin interactions between A-type (active) and B-type (inactive) compartments increase significantly but those among same types of compartments decrease significantly, which associate with global gene expression changes. While TADs remain largely invariant, both inter- and intra-TAD interactions increase significantly in A-type compartments but decrease in B-type compartments. Mechanically, HNRNPU complexes with structural proteins CTCF and RAD21; depletion of HNRNPU specifically weakens the bindings of RAD21 to the chromatin, which is highly correlated with the weakness of chromatin loops.
2017-12-03 | GSE95112 | GEO