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Extracellular Matrix Stiffness Regulates DNA Methylation by PKC α ‐Dependent Nuclear Transport of DNMT3L
Author(s) -
Zhao XinBin,
Chen YunPing,
Tan Min,
Zhao Lan,
Zhai YuanYuan,
Sun YanLing,
Gong Yan,
Feng XiQiao,
Du Jing,
Fan YuBo
Publication year - 2021
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.202100821
Subject(s) - dna methylation , extracellular matrix , microbiology and biotechnology , epigenetics , homeobox protein nanog , biology , dna methyltransferase , embryonic stem cell , gene expression , chemistry , gene , induced pluripotent stem cell , genetics
Extracellular matrix (ECM) stiffness has profound effects on the regulation of cell functions. DNA methylation is an important epigenetic modification governing gene expression. However, the effects of ECM stiffness on DNA methylation remain elusive. Here, it is reported that DNA methylation is sensitive to ECM stiffness, with a global hypermethylation under stiff ECM condition in mouse embryonic stem cells (mESCs) and embryonic fibroblasts compared with soft ECM. Stiff ECM enhances DNA methylation of both promoters and gene bodies, especially the 5’ promoter regions of pluripotent genes. The enhanced DNA methylation is functionally required for the loss of pluripotent gene expression in mESCs grown on stiff ECM. Further experiments reveal that the nuclear transport of DNA methyltransferase 3‐like (DNMT3L) is promoted by stiff ECM in a protein kinase C α (PKC α )‐dependent manner and DNMT3L can be binding to Nanog promoter regions during cell–ECM interactions. These findings unveil DNA methylation as a novel target for the mechanical sensing mechanism of ECM stiffness, which provides a conserved mechanism for gene expression regulation during cell–ECM interactions.