Biphasic regulation of epigenetic state by matrix stiffness during cell reprogramming-Reference-Cited by-同舟云学术

Biphasic regulation of epigenetic state by matrix stiffness during cell reprogramming

Published:2024-02-16 Issue:7 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Song Yang¹^ORCID,Soto Jennifer¹,Wong Sze Yue²,Wu Yifan¹,Hoffman Tyler¹,Akhtar Navied³,Norris Sam¹,Chu Julia²,Park Hyungju⁴⁵^ORCID,Kelkhoff Douglas O.²^ORCID,Ang Cheen Euong⁶⁷,Wernig Marius⁷^ORCID,Kasko Andrea¹^ORCID,Downing Timothy L.³^ORCID,Poo Mu-ming⁴⁸^ORCID,Li Song¹⁹¹⁰¹¹^ORCID

Affiliation:

1. Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

2. Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.

3. Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.

4. Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.

5. Department of Structure and Function of Neural Network, Korea Brain Research Institute (KBRI), Daegu 41068, South Korea.

6. Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.

7. Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.

8. Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

9. Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

10. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.

11. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adk0639

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