Journal
NATURE BIOMEDICAL ENGINEERING
Volume 1, Issue 11, Pages 902-913Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41551-017-0153-2
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Funding
- National Science Foundation Graduate Research Fellowship [DGE-0824162]
- National Institutes of Health T32 training grants [T32GM008152, T32HL076139]
- Lefkofsky Innovation Award
- Robert H. Lurie Comprehensive Cancer Center Translational Bridge Award
- Chicago Biomedical Consortium
- Searle Funds at The Chicago Community Trust
- National Institute of Health through Chicago Region Physical Science Oncology Center [U54CA193419]
- NCI [CA060553]
- National Science Foundation [EFRI-1240416]
- [R01CA200064]
- [R01CA165309]
- [R01EB016983]
- Directorate For Engineering
- Emerging Frontiers & Multidisciplinary Activities [1240416] Funding Source: National Science Foundation
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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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