Reduction of Intracellular Tension and Cell Adhesion Promotes Open Chromatin Structure and Enhances Cell Reprogramming

被引:15
作者
Soto, Jennifer [1 ]
Song, Yang [1 ]
Wu, Yifan [1 ]
Chen, Binru [1 ]
Park, Hyungju [2 ]
Akhtar, Navied [3 ]
Wang, Peng-Yuan [1 ,4 ]
Hoffman, Tyler [1 ]
Ly, Chau [1 ,5 ]
Sia, Junren [6 ]
Wong, SzeYue [6 ]
Kelkhoff, Douglas O. [6 ]
Chu, Julia [6 ]
Poo, Mu-Ming [2 ]
Downing, Timothy L. [3 ]
Rowat, Amy C. [1 ,5 ]
Li, Song [1 ,7 ,8 ,9 ]
机构
[1] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA 90095 USA
[2] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
[3] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92617 USA
[4] Wenzhou Med Univ, Inst Aging, Oujiang Lab, Key Lab Alzheimers Dis Zhejiang Prov, Wenzhou 325024, Zhejiang, Peoples R China
[5] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA
[6] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA
[7] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA
[8] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell R, Los Angeles, CA 90095 USA
[9] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, David Geffen Sch Med, Los Angeles, CA 90095 USA
基金
美国国家科学基金会;
关键词
cell adhesion; cytoskeleton; direct reprogramming; epigenetic state; PLURIPOTENT STEM-CELLS; BIOPHYSICAL REGULATION; NEURONAL CELLS; FIBROBLASTS; MECHANOTRANSDUCTION; TECHNOLOGIES; MECHANISMS; EFFICIENCY; INHIBITOR; ORIGINS;
D O I
10.1002/advs.202300152
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The role of transcription factors and biomolecules in cell type conversion has been widely studied. Yet, it remains unclear whether and how intracellular mechanotransduction through focal adhesions (FAs) and the cytoskeleton regulates the epigenetic state and cell reprogramming. Here, it is shown that cytoskeletal structures and the mechanical properties of cells are modulated during the early phase of induced neuronal (iN) reprogramming, with an increase in actin cytoskeleton assembly induced by Ascl1 transgene. The reduction of actin cytoskeletal tension or cell adhesion at the early phase of reprogramming suppresses the expression of mesenchymal genes, promotes a more open chromatin structure, and significantly enhances the efficiency of iN conversion. Specifically, reduction of intracellular tension or cell adhesion not only modulates global epigenetic marks, but also decreases DNA methylation and heterochromatin marks and increases euchromatin marks at the promoter of neuronal genes, thus enhancing the accessibility for gene activation. Finally, micro- and nano-topographic surfaces that reduce cell adhesions enhance iN reprogramming. These novel findings suggest that the actin cytoskeleton and FAs play an important role in epigenetic regulation for cell fate determination, which may lead to novel engineering approaches for cell reprogramming.
引用
收藏
页数:20
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