It is increasingly evident that both soluble factor-mediated chemical signaling and physical force-mediated mechanotransduction play critical roles in living cells and tissues. Yet we know relatively little about how force regulates gene expression and vital biological functions. Mechanosensors at or near the cell surface such as integrin, talin, or vinculin have been reported, but whether the nucleus itself and its chromatin can act as a mechanosensor is an unanswered question in the field of mechanobiology. Yet regulation of gene expression in normal cells and cancer cells is one of the most critical processes that control cellular functions and behaviors. This research project aims to understand how forces and mechanical microenvironment directly influence gene expression and to identify intra-nuclear proteins that are responsible for mediating force transfer from nuclear lamina to lamina-associated domains of chromatin in living cells. Our preliminary results strongly suggest that a local physiologically-relevant force via integrins can directly upregulation transcription via stretching the chromatin in living cells. Built on these results, we propose 3 specific aims to elucidate mechanotransduction mechanisms in the living cells.
Aim 1 : to test the hypothesis that chromatin stretching is required for direct transcription upregulation by force via integrins;
Aim 2 : to test the hypothesis that force via integrins directly activates mechanosensitive genes more than housekeeping gene DHFR;
Aim 3 : to dissect out the mechanism of gene repression in response to high forces and on stiff matrices. Our experimental designs are rigorous and the likelihood of generating insightful discovery is very high. The long-term goal is to develop novel strategies to intervene the processes that regulate gene expression in living cells in animals and human subjects to treat and cure diseases like malignant tumors.

Public Health Relevance

How gene expression is controlled and regulated by mechanical forces is not well understood. Yet regulation of gene expression in normal cells and cancer cells is one of the most critical processes that control cellular functions and behaviors. This research project aims to understand how forces and mechanical microenvironment directly influence gene expression, relevant for developing future novel strategies to intervene the processes that regulate gene expression in living cells in human malignant tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072744-16
Application #
9929587
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Flicker, Paula F
Project Start
2005-08-01
Project End
2023-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
16
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Chowdhury, Farhan; Do?anay, Sultan; Leslie, Benjamin J et al. (2018) Cdc42-dependent modulation of rigidity sensing and cell spreading in tumor repopulating cells. Biochem Biophys Res Commun 500:557-563
Zhang, Yuejin; Wei, Fuxiang; Poh, Yeh-Chuin et al. (2017) Interfacing 3D magnetic twisting cytometry with confocal fluorescence microscopy to image force responses in living cells. Nat Protoc 12:1437-1450
Wang, Ning (2017) Review of Cellular Mechanotransduction. J Phys D Appl Phys 50:
Tan, Youhua; Wood, Adam Richard; Jia, Qiong et al. (2017) Soft matrices downregulate FAK activity to promote growth of tumor-repopulating cells. Biochem Biophys Res Commun 483:456-462
Ma, Jingwei; Zhang, Yi; Tang, Ke et al. (2016) Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles. Cell Res 26:713-27
Jia, Q; Zhou, W; Yao, W et al. (2016) Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices. Oncogenesis 5:e220
Muhamed, Ismaeel; Wu, Jun; Sehgal, Poonam et al. (2016) E-cadherin-mediated force transduction signals regulate global cell mechanics. J Cell Sci 129:1843-54
Tajik, Arash; Zhang, Yuejin; Wei, Fuxiang et al. (2016) Transcription upregulation via force-induced direct stretching of chromatin. Nat Mater 15:1287-1296
Chen, Junjian; Zhou, Wenwen; Jia, Qiong et al. (2016) Efficient extravasation of tumor-repopulating cells depends on cell deformability. Sci Rep 6:19304
Li, Yong; Luo, Shunqun; Ma, Ruihua et al. (2015) Upregulation of cytosolic phosphoenolpyruvate carboxykinase is a critical metabolic event in melanoma cells that repopulate tumors. Cancer Res 75:1191-6

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