Macrogenomic engineering via modulation of the scaling of chromatin packing density

Luay M. Almassalha; Greta M. Bauer; Wenli Wu; Lusik Cherkezyan; Di Zhang; Alexis Kendra; Scott Gladstein; John E. Chandler; David Vanderway; Brandon Luke L. Seagle; Andrey Ugolkov; Daniel D. Billadeau; Thomas V. O'Halloran; Andrew P. Mazar; Hemant K. Roy; Igal Szleifer; Shohreh Shahabi; Vadim Backman

doi:10.1038/s41551-017-0153-2

Macrogenomic engineering via modulation of the scaling of chromatin packing density

Luay M. Almassalha, Greta M. Bauer, Wenli Wu, Lusik Cherkezyan, Di Zhang, Alexis Kendra, Scott Gladstein, John E. Chandler, David Vanderway, Brandon Luke L. Seagle, Andrey Ugolkov, Daniel D. Billadeau, Thomas V. O'Halloran, Andrew P. Mazar, Hemant K. Roy, Igal Szleifer^*, Shohreh Shahabi, Vadim Backman

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English (US)
Pages (from-to)	902-913
Number of pages	12
Journal	Nature Biomedical Engineering
Volume	1
Issue number	11
DOIs	https://doi.org/10.1038/s41551-017-0153-2
State	Published - Nov 1 2017

Funding

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.

ASJC Scopus subject areas

Bioengineering
Biotechnology
Biomedical Engineering
Medicine (miscellaneous)
Computer Science Applications

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41551-017-0153-2

Cite this

Almassalha, L. M., Bauer, G. M., Wu, W., Cherkezyan, L., Zhang, D., Kendra, A., Gladstein, S., Chandler, J. E., Vanderway, D., Seagle, B. L. L., Ugolkov, A., Billadeau, D. D., O'Halloran, T. V., Mazar, A. P., Roy, H. K., Szleifer, I., Shahabi, S., & Backman, V. (2017). Macrogenomic engineering via modulation of the scaling of chromatin packing density. Nature Biomedical Engineering, 1(11), 902-913. https://doi.org/10.1038/s41551-017-0153-2

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title = "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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Almassalha, LM, Bauer, GM, Wu, W, Cherkezyan, L, Zhang, D, Kendra, A, Gladstein, S, Chandler, JE, Vanderway, D, Seagle, BLL, Ugolkov, A, Billadeau, DD, O'Halloran, TV, Mazar, AP, Roy, HK, Szleifer, I , Shahabi, S & Backman, V 2017, 'Macrogenomic engineering via modulation of the scaling of chromatin packing density', Nature Biomedical Engineering, vol. 1, no. 11, pp. 902-913. https://doi.org/10.1038/s41551-017-0153-2

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AU - Almassalha, Luay M.

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AU - Zhang, Di

AU - Kendra, Alexis

AU - Gladstein, Scott

AU - Chandler, John E.

AU - Vanderway, David

AU - Seagle, Brandon Luke L.

AU - Ugolkov, Andrey

AU - Billadeau, Daniel D.

AU - O'Halloran, Thomas V.

AU - Mazar, Andrew P.

AU - Roy, Hemant K.

AU - Szleifer, Igal

AU - Shahabi, Shohreh

AU - Backman, Vadim

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Macrogenomic engineering via modulation of the scaling of chromatin packing density

Abstract

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UN SDGs

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