Biphasic regulation of epigenetic state by matrix stiffness during cell reprogramming

被引：13

作者：

Song, Yang ^{[1
]}

Soto, Jennifer ^{[1
]}

Wong, Sze Yue ^{[2
]}

Wu, Yifan ^{[1
]}

Hoffman, Tyler ^{[1
]}

Akhtar, Navied ^{[3
]}

Norris, Sam ^{[1
]}

Chu, Julia ^{[2
]}

Park, Hyungju ^{[4
,5
]}

Kelkhoff, Douglas O. ^{[2
]}

Ang, Cheen Euong ^{[6
,7
,8
]}

Wernig, Marius ^{[7
,8
]}

Kasko, Andrea ^{[1
]}

Downing, Timothy L. ^{[3
]}

Poo, Mu-ming ^{[4
,9
]}

Li, Song ^{[1
,10
,11
,12
]}

机构：

[1] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA 90095 USA

[2] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA

[3] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92617 USA

[4] Univ Calif Berkeley, Helen Wills Neurosci Inst, Dept Mol & Cell Biol, Div Neurobiol, Berkeley, CA 94720 USA

[5] Korea Brain Res Inst KBRI, Dept Struct & Funct Neural Network, Daegu 41068, South Korea

[6] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[8] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[9] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, Shanghai 200031, Peoples R China

[10] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell R, Los Angeles, CA 90095 USA

[12] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

来源：

SCIENCE ADVANCES | 2024年 / 10卷 / 07期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

EXTRACELLULAR-MATRIX; BIOPHYSICAL REGULATION; MECHANICAL-PROPERTIES; GENE-EXPRESSION; FIBROBLASTS; ACTIN; SHAPE;

D O I：

10.1126/sciadv.adk0639

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

We investigate how matrix stiffness regulates chromatin reorganization and cell reprogramming and find that matrix stiffness acts as a biphasic regulator of epigenetic state and fibroblast-to-neuron conversion efficiency, maximized at an intermediate stiffness of 20 kPa. ATAC sequencing analysis shows the same trend of chromatin accessibility to neuronal genes at these stiffness levels. Concurrently, we observe peak levels of histone acetylation and histone acetyltransferase (HAT) activity in the nucleus on 20 kPa matrices, and inhibiting HAT activity abolishes matrix stiffness effects. G-actin and cofilin, the cotransporters shuttling HAT into the nucleus, rises with decreasing matrix stiffness; however, reduced importin-9 on soft matrices limits nuclear transport. These two factors result in a biphasic regulation of HAT transport into nucleus, which is directly demonstrated on matrices with dynamically tunable stiffness. Our findings unravel a mechanism of the mechano-epigenetic regulation that is valuable for cell engineering in disease modeling and regenerative medicine applications.

引用

页数：16

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