The ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cells
Scholz, Barbara A
Fernandez Woodbridge, Alejandro
Kiani, Narsis A.
Svensson, J Peter
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
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AbstractThe 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.
CitationSumida N, Sifakis E, Scholz BA, Fernandez Woodbridge A, Kiani N, et al. (2018) The ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cells. Available: http://dx.doi.org/10.1101/286583.
SponsorsThe authors would like to acknowledge support from Science for Life Laboratory, the National Genomics Infrastructure, NGI, and Uppmax for providing assistance in massive parallel sequencing and computational infrastructure as well as the extensive data sets from ENCODE. This work was supported by the Swedish Cancer Foundation (CAN2016/576 (AG); CAN2016/616 (JPS), VR-NT (2013-4511 (RO)), VR-M (2015-02312 (PS); 2014-3683 (RO); 2016-03108 (AG)), Karolinska Institutet (AG, RO), Åke Wiberg Stiftelse (M16-0090; AG)), Swedish Pediatric Cancer Foundation (2015-0129; AG)), and the KA Wallenberg Foundation (Clinical Epigenetics; RO).
PublisherCold Spring Harbor Laboratory