Extracellular Matrix Stiffness Regulates DNA Methylatioan by PKCα-Dependent Nuclear Transport of DNMT3L

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 alpha (PKC alpha)-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.

Automated summary

ECM stiffness affects DNA methylation, with a global hypermethylation observed under stiff ECM conditions, particularly in the 5' promoter regions of pluripotent genes. Enhanced DNA methylation is functionally required for the loss of pluripotent gene expression in mESCs grown on stiff ECM. The nuclear transport of DNMT3L is promoted by stiff ECM in a PKC alpha-dependent manner, and DNMT3L binds to Nanog promoter regions during cell-ECM interactions. These findings reveal DNA methylation as a novel target for the mechanical sensing mechanism of ECM stiffness, providing a conserved mechanism for gene expression regulation during cell-ECM interactions.