The ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens Drosophila melanogaster
PROVIDER: GSE76049 | GEO | 2019/09/30
REPOSITORIES: GEO
Similar Datasets
Project description:The relationship between stochastic transcriptional bursts and dynamic 3D chromatin states is not well understood due to poor sensitivity and/or resolution of current chromatin structure-based assays. Consequently, it is not well established if enhancers operate individually and/or in clusters to coordinate gene transcription. In the current study, we introduce Nodewalk, which uniquely combines high sensitivity with high resolution to enable the analysis of chromatin networks in minute input material. The >10,000-fold increase in sensitivity over other many-to-all competing methods uncovered that active chromatin hubs identified in large input material, corresponding to 10 000 cells, flanking the MYC locus are primarily virtual. Thus, the close agreement between chromatin interactomes generated from aliquots corresponding to less than 10 cells with randomly re-sampled interactomes, we find that numerous distal enhancers positioned within flanking topologically associating domains (TADs) converge on MYC in largely mutually exclusive manners. Moreover, when comparing with several enhancer baits, the assignment of the MYC locus as the node with the highest dynamic importance index, indicates that it is MYC targeting its enhancers, rather than vice versa. Dynamic changes in the configuration of the boundary between TADs flanking MYC underlie numerous stochastic encounters with a diverse set of enhancers to depict the plasticity of its transcriptional regulation. Such an arrangement might increase the fitness of the cancer cell by increasing the probability of MYC transcription in response to a wide range of environmental cues encountered by the cell during the neoplastic process.
2019-09-30 | GSE76038 | GEO
Project description:The relationship between stochastic transcriptional bursts and dynamic 3D chromatin states is not well understood due to poor sensitivity and/or resolution of current chromatin structure-based assays. Consequently, it is not well established if enhancers operate individually and/or in clusters to coordinate gene transcription. In the current study, we introduce Nodewalk, which uniquely combines high sensitivity with high resolution to enable the analysis of chromatin networks in minute input material. The >10,000-fold increase in sensitivity over other many-to-all competing methods uncovered that active chromatin hubs identified in large input material, corresponding to 10 000 cells, flanking the MYC locus are primarily virtual. Thus, the close agreement between chromatin interactomes generated from aliquots corresponding to less than 10 cells with randomly re-sampled interactomes, we find that numerous distal enhancers positioned within flanking topologically associating domains (TADs) converge on MYC in largely mutually exclusive manners. Moreover, when comparing with several enhancer baits, the assignment of the MYC locus as the node with the highest dynamic importance index, indicates that it is MYC targeting its enhancers, rather than vice versa. Dynamic changes in the configuration of the boundary between TADs flanking MYC underlie numerous stochastic encounters with a diverse set of enhancers to depict the plasticity of its transcriptional regulation. Such an arrangement might increase the fitness of the cancer cell by increasing the probability of MYC transcription in response to a wide range of environmental cues encountered by the cell during the neoplastic process.
2019-09-30 | GSE76041 | GEO
Project description:The relationship between stochastic transcriptional bursts and dynamic 3D chromatin states is not well understood due to poor sensitivity and/or resolution of current chromatin structure-based assays. Consequently, it is not well established if enhancers operate individually and/or in clusters to coordinate gene transcription. In the current study, we introduce Nodewalk, which uniquely combines high sensitivity with high resolution to enable the analysis of chromatin networks in minute input material. The >10,000-fold increase in sensitivity over other many-to-all competing methods uncovered that active chromatin hubs identified in large input material, corresponding to 10 000 cells, flanking the MYC locus are primarily virtual. Thus, the close agreement between chromatin interactomes generated from aliquots corresponding to less than 10 cells with randomly re-sampled interactomes, we find that numerous distal enhancers positioned within flanking topologically associating domains (TADs) converge on MYC in largely mutually exclusive manners. Moreover, when comparing with several enhancer baits, the assignment of the MYC locus as the node with the highest dynamic importance index, indicates that it is MYC targeting its enhancers, rather than vice versa. Dynamic changes in the configuration of the boundary between TADs flanking MYC underlie numerous stochastic encounters with a diverse set of enhancers to depict the plasticity of its transcriptional regulation. Such an arrangement might increase the fitness of the cancer cell by increasing the probability of MYC transcription in response to a wide range of environmental cues encountered by the cell during the neoplastic process.
2019-09-30 | GSE76048 | GEO
Project description:The relationship between stochastic transcriptional bursts and dynamic 3D chromatin states is not well understood due to poor sensitivity and/or resolution of current chromatin structure-based assays. Consequently, it is not well established if enhancers operate individually and/or in clusters to coordinate gene transcription. In the current study, we introduce Nodewalk, which uniquely combines high sensitivity with high resolution to enable the analysis of chromatin networks in minute input material. The >10,000-fold increase in sensitivity over other many-to-all competing methods uncovered that active chromatin hubs identified in large input material, corresponding to 10 000 cells, flanking the MYC locus are primarily virtual. Thus, the close agreement between chromatin interactomes generated from aliquots corresponding to less than 10 cells with randomly re-sampled interactomes, we find that numerous distal enhancers positioned within flanking topologically associating domains (TADs) converge on MYC in largely mutually exclusive manners. Moreover, when comparing with several enhancer baits, the assignment of the MYC locus as the node with the highest dynamic importance index, indicates that it is MYC targeting its enhancers, rather than vice versa. Dynamic changes in the configuration of the boundary between TADs flanking MYC underlie numerous stochastic encounters with a diverse set of enhancers to depict the plasticity of its transcriptional regulation. Such an arrangement might increase the fitness of the cancer cell by increasing the probability of MYC transcription in response to a wide range of environmental cues encountered by the cell during the neoplastic process.
2019-09-30 | GSE76043 | GEO
Project description:The ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cells [Nodewalk-seq]
| PRJNA306059 | ENA
Project description:The ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cells
| PRJNA306055 | ENA
Project description:Mass sensors based on the eigenmode shift of coupled cantilevers achieve much higher sensitivity than those based on the single cantilever's eigenfrequency shift. In the former sensors, two identical cantilevers and a weak coupling stiffness between them are required to achieve high sensitivity. However, conventional coupled cantilevers cannot satisfy these requirements because of machining accuracy. To satisfy both requirements, a virtual coupling between a real macrocantilever and a virtual cantilever, whose dynamics was calculated using a digital computer, was proposed in our previous research. The sensitive mass sensing of mg-order masses was achieved. In the present work, for minute mass sensing, we replace the real macrocantilever with a real microcantilever. The calculation speed of a digital computer is not fast enough to calculate the virtual cantilever's dynamics because the natural frequency of the microcantilver is much higher than that of the macrocantilever. Therefore, we use an analog circuit instead of a digital computer to achieve virtual coupling with the virtual cantilever. The proposed system enables us to tune the virtual cantilever's parameters to satisfy both requirements for high sensitivity by changing the analog circuit parameters. We verified experimentally that the proposed system achieved high sensitivity for mass sensing of the order of nanograms.
| S-EPMC7180872 | biostudies-literature
Project description:The relationship between stochastic transcriptional bursts and dynamic 3D chromatin states is not well understood. Using an innovated, ultra-sensitive technique, we address here enigmatic features underlying the communications between MYC and its enhancers in relation to the transcriptional process. MYC thus interacts with its flanking enhancers in a mutually exclusive manner documenting that enhancer hubs impinging on MYC detected in large cell populations likely do not exist in single cells. Dynamic encounters with pathologically activated enhancers responsive to a range of environmental cues, involved <10% of active MYC alleles at any given time in colon cancer cells. Being the most central node of the chromatin network, MYC itself likely drives its communications with flanking enhancers, rather than vice versa. We submit that these features underlie an acquired ability of MYC to become dynamically activated in response to a diverse range of environmental cues encountered by the cell during the neoplastic process.
| S-EPMC7641766 | biostudies-literature
Project description:Many proteins assemble into homomultimeric structures, with a number of subunits that can vary substantially among phylogenetic lineages. As protein-protein interactions require productive encounters among subunits, such variation might partially be explained by variation in cellular protein abundance. Protein abundance in turn depends on the intrinsic rates of production and decay of mRNA and protein molecules, as well as rates of cell growth and division. Using a stochastic framework for prediction of the multimeric state of a protein as a function of these processes and the free energy associated with interface-interface binding, we demonstrate agreement with a wide class of proteins using E. coli proteome data. As such, this platform, which links protein quaternary structure with biochemical rates governing gene expression, protein association and dissociation, and cell growth and division, can be extended to evolutionary models for the emergence and diversification of multimers. While it is tempting to think of multimerization as adaptive, the diversity of multimeric states raises the question of its functional role and impact on fitness. As a force driving selection, we consider the possible increase in enzymatic activity of proteins arising strictly as a consequence of interface-interface binding-namely, enhanced stability to degradation, substrate binding affinity, or catalytic rate of multimers with respect to monomers without invoking further conformational changes, as in allostery. For fixed cost of protein production, we find a benefit conferred by multimers that is dependent on context and can therefore become different in diverging lineages.
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Project description:In the framework of coding theory, under the assumption of a Markov process (Xt) on a finite alphabet A, the compressed representation of the data will be composed of a description of the model used to code the data and the encoded data. Given the model, the Huffman's algorithm is optimal for the number of bits needed to encode the data. On the other hand, modeling (Xt) through a Partition Markov Model (PMM) promotes a reduction in the number of transition probabilities needed to define the model. This paper shows how the use of Huffman code with a PMM reduces the number of bits needed in this process. We prove the estimation of a PMM allows for estimating the entropy of (Xt), providing an estimator of the minimum expected codeword length per symbol. We show the efficiency of the new methodology on a simulation study and, through a real problem of compression of DNA sequences of SARS-CoV-2, obtaining in the real data at least a reduction of 10.4%.
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