The ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cells

Handle URI:
http://hdl.handle.net/10754/627411
Title:
The ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cells
Authors:
Sumida, Noriyuki ( 0000-0001-6121-4553 ) ; Sifakis, Emmanouil ( 0000-0003-2618-9131 ) ; Scholz, Barbara A ( 0000-0003-2364-8304 ) ; Fernandez Woodbridge, Alejandro; Kiani, Narsis ( 0000-0002-0949-046X ) ; Gomez-Cabrero, David ( 0000-0003-4186-3788 ) ; Svensson, J Peter ( 0000-0002-5863-6250 ) ; Tegner, Jesper ( 0000-0002-9568-5588 ) ; Gondor, Anita ( 0000-0002-1523-4411 ) ; Ohlsson, Rolf ( 0000-0001-7308-3300 )
Abstract:
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.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Citation:
Sumida 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.
Publisher:
Cold Spring Harbor Laboratory
Issue Date:
27-Mar-2018
DOI:
10.1101/286583
Type:
Working Paper
Sponsors:
The 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).
Additional Links:
https://www.biorxiv.org/content/early/2018/03/27/286583
Appears in Collections:
Other/General Submission; Bioscience Program; Biological and Environmental Sciences and Engineering (BESE) Division; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorSumida, Noriyukien
dc.contributor.authorSifakis, Emmanouilen
dc.contributor.authorScholz, Barbara Aen
dc.contributor.authorFernandez Woodbridge, Alejandroen
dc.contributor.authorKiani, Narsisen
dc.contributor.authorGomez-Cabrero, Daviden
dc.contributor.authorSvensson, J Peteren
dc.contributor.authorTegner, Jesperen
dc.contributor.authorGondor, Anitaen
dc.contributor.authorOhlsson, Rolfen
dc.date.accessioned2018-04-04T12:38:14Z-
dc.date.available2018-04-04T12:38:14Z-
dc.date.issued2018-03-27en
dc.identifier.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.en
dc.identifier.doi10.1101/286583en
dc.identifier.urihttp://hdl.handle.net/10754/627411-
dc.description.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.en
dc.description.sponsorshipThe 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).en
dc.publisherCold Spring Harbor Laboratoryen
dc.relation.urlhttps://www.biorxiv.org/content/early/2018/03/27/286583en
dc.rightsArchived with thanks to bioRxiven
dc.subjectChromatinen
dc.subjecttranscriptionen
dc.subjectnetworksen
dc.subjectTopologyen
dc.titleThe ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cellsen
dc.typeWorking Paperen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentBioscience Programen
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Divisionen
dc.eprint.versionPre-printen
dc.contributor.institutionDepartment of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Z1:00, SE-171 76 Stockholm, Swedenen
dc.contributor.institutionUnit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, L8:05, SE-171 76, Stockholm, Swedenen
dc.contributor.institutionMucosal and Salivary Biology Division, King’s College London Dental Institute, London, SE1 9RT, United Kingdomen
dc.contributor.institutionDepartment of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Swedenen
dc.contributor.institutionScience for Life Laboratory, Tomtebodavägen 23A, SE-17165, Solna, Swedenen
kaust.authorTegner, Jesperen
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