Macrogenomic engineering via modulation of the scaling of chromatin packing density

Abstract

Many human diseases result from the dysregulation of the complex interactions between tens to thousands of genes. However, approaches for the transcriptional modulation of many genes simultaneously in a predictive manner are lacking. Here, through the combination of simulations, systems modelling and in vitro experiments, we provide a physical regulatory framework based on chromatin packing-density heterogeneity for modulating the genomic information space. Because transcriptional interactions are essentially chemical reactions, they depend largely on the local physical nanoenvironment. We show that the regulation of the chromatin nanoenvironment allows for the predictable modulation of global patterns in gene expression. In particular, we show that the rational modulation of chromatin density fluctuations can lead to a decrease in global transcriptional activity and intercellular transcriptional heterogeneity in cancer cells during chemotherapeutic responses to achieve near-complete cancer cell killing in vitro. Our findings represent a ‘macrogenomic engineering’ approach to modulating the physical structure of chromatin for whole-scale transcriptional modulation.

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Fig. 1: Genomic networks are highly interconnected and decentralized.
Fig. 2: Genomic interactions depend on a complex physical nanoenvironment.
Fig. 3: Control of higher-order chromatin packing density scaling allows manipulation of genomic information space.
Fig. 4: Chemotherapeutic stress increases variations in chromatin packing density.
Fig. 5: Chromatin protective agents rapidly decrease the spatial variations in chromatin packing density.
Fig. 6: Regulation of chromatin packing-density scaling modulates transcriptional heterogeneity.
Fig. 7: Rapid modulation of chromatin packing density scaling by CPT agents greatly enhances chemotherapeutic efficacy.

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Acknowledgements

This work has been supported by the National Science Foundation grant EFRI-1240416, the National Science Foundation Graduate Research Fellowship grant DGE-0824162, National Institutes of Health T32 training grants T32GM008152 and T32HL076139, the Lefkofsky Innovation Award, The Robert H. Lurie Comprehensive Cancer Center Translational Bridge Award, the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust, the National Institute of Health through the Chicago Region Physical Science Oncology Center U54CA193419, as well as grants R01CA200064, R01CA165309, and R01EB016983. Flow Cytometry was performed by the Northwestern University Flow Cytometry Facility, which has received support from NCI CA060553.

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T.V.O., A.P.M., H.K.R., I.S., S.S. and V.B. conceived the research; L.C., J.E.C. and V.B. developed the PWS instrumentation; G.M.B., W.W., L.M.A., A.K., S.G. and D.V. performed the experiments, molecular dynamics simulations and mathematical modelling; Andrey Ugolkov (A.U.) and Daniel D. Billadeau (D.D.B.) contributed to the design of experiments;  G.M.B., W.W., L.M.A. and V.B. wrote the original draft; G.M.B., L.M.A., L.C., A.K., S.G., J.E.C., B.-L.L.S., T.V.O., H.K.R., I.S., S.S. and V.B. reviewed and edited the paper.

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Correspondence to Igal Szleifer or Vadim Backman.

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Macrogenomic model and analysis, and supplementary figures and references

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Supplementary Table 1

Microarray source data for Fig. 3 and Supplementary Fig. 5

Supplementary Table 2

Normalized Σ values for Figs. 4 and 5 and Supplementary Figs. 1 and 2

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Almassalha, L.M., Bauer, G.M., Wu, W. et al. Macrogenomic engineering via modulation of the scaling of chromatin packing density. Nat Biomed Eng 1, 902–913 (2017). https://doi.org/10.1038/s41551-017-0153-2

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