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Biphasic regulation of epigenetic state by matrix stiffness during cell reprogramming.
Song, Yang; Soto, Jennifer; Wong, Sze Yue; Wu, Yifan; Hoffman, Tyler; Akhtar, Navied; Norris, Sam; Chu, Julia; Park, Hyungju; Kelkhoff, Douglas O; Ang, Cheen Euong; Wernig, Marius; Kasko, Andrea; Downing, Timothy L; Poo, Mu-Ming; Li, Song.
Afiliação
  • Song Y; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Soto J; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Wong SY; Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Wu Y; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Hoffman T; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Akhtar N; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.
  • Norris S; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Chu J; Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Park H; Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Kelkhoff DO; Department of Structure and Function of Neural Network, Korea Brain Research Institute (KBRI), Daegu 41068, South Korea.
  • Ang CE; Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Wernig M; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Kasko A; Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
  • Downing TL; Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
  • Poo MM; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Li S; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.
Sci Adv ; 10(7): eadk0639, 2024 Feb 16.
Article em En | MEDLINE | ID: mdl-38354231
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Reprogramação Celular Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Reprogramação Celular Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2024 Tipo de documento: Article