Macrogenomic engineering via modulation of the scaling of chromatin packing density

被引：34

作者：

Almassalha, Luay M. ^{[1
]}

Bauer, Greta M. ^{[1
]}

Wu, Wenli ^{[1
]}

Cherkezyan, Lusik ^{[1
]}

Zhang, Di ^{[1
]}

Kendra, Alexis ^{[1
]}

Gladstein, Scott ^{[1
]}

Chandler, John E. ^{[1
]}

VanDerway, David ^{[1
]}

Seagle, Brandon-Luke L. ^{[2
]}

Ugolkov, Andrey ^{[3
]}

Billadeau, Daniel D. ^{[4
]}

O'Halloran, Thomas V. ^{[3
,5
,6
]}

Mazar, Andrew P. ^{[7
]}

Roy, Hemant K. ^{[8
]}

Szleifer, Igal ^{[1
,3
,5
]}

Shahabi, Shohreh ^{[2
]}

Backman, Vadim ^{[1
,3
]}

机构：

[1] Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA

[2] Northwestern Univ, Prentice Womens Hosp, Dept Obstet & Gynecol, Feinberg Sch Med, Chicago, IL 60611 USA

[3] Northwestern Univ, Chem Life Proc Inst, Evanston, IL 60208 USA

[4] Mayo Clin, Div Oncol Res, Schulze Ctr Novel Therapeut, Rochester, MN 55905 USA

[5] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA

[6] Northwestern Univ, Dept Chem, 2145 Sheridan Rd, Evanston, IL 60208 USA

[7] Monopar Therapeut Inc, Northbrook, IL 60062 USA

[8] Boston Univ, Sch Med, Boston Med Ctr, Sect Gastroenterol, Boston, MA 02118 USA

来源：

NATURE BIOMEDICAL ENGINEERING | 2017年 / 1卷 / 11期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

HUMAN-GENOME; NANOCYTOLOGY; ORGANIZATION; CONSEQUENCES; COLONOCYTES; EXPRESSION; PRINCIPLES; IMPACT; RISK;

D O I：

10.1038/s41551-017-0153-2

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

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.

引用

页码：902 / 913

页数：12

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