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

Research output: Contribution to journalArticle

15 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 languageEnglish (US)
Pages (from-to)902-913
Number of pages12
JournalNature Biomedical Engineering
Volume1
Issue number11
DOIs
StatePublished - Nov 1 2017

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ASJC Scopus subject areas

  • Biomedical Engineering
  • Biotechnology
  • Bioengineering
  • Medicine (miscellaneous)
  • Computer Science Applications

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