Regulation of heterochromatin remodelling and myogenin expression during muscle differentiation by FAK interaction with MBD2.
Focal adhesion kinase (FAK), a major cell adhesion-activated tyrosine kinase, has an important function in cell adhesion and migration. Here, we report a new signalling of FAK in regulating chromatin remodelling by its interaction with MBD2 (methyl CpG-binding protein 2), underlying FAK regulation of myogenin expression and muscle differentiation. FAK interacts with MBD2 in vitro, in myotubes, and in isolated muscle fibres. Such an interaction, increased in myotubes exposed to oxidative stress, enhances FAK nuclear localization. The nuclear FAK-MBD2 complexes alter heterochromatin reorganization and decrease MBD2 association with HDAC1 (histone deacetylase complex 1) and methyl CpG site in the myogenin promoter, thus, inducing myogenin expression. In line with this view are observations that blocking FAK nuclear localization by expressing dominant negative MBD2 or suppression of FAK expression by its miRNA in C2C12 cells attenuates myogenin induction and/or impairs muscle-terminal differentiation. Together, these results suggest an earlier unrecognized role of FAK in regulating chromatin remodelling that is important for myogenin expression and muscle-terminal differentiation, reveal a new mechanism of MBD2 regulation by FAK family tyrosine kinases, and provide a link between cell adhesion and chromatin remodelling.
Luo
Shi-Wen
SW
Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
Zhang
Chun
C
Zhang
Bin
B
Kim
Chang-Hoon
CH
Qiu
Yuan-Zheng
YZ
Du
Quan-Sheng
QS
Mei
Lin
L
Xiong
Wen-Cheng
WC
D001665:Binding Sites; D002454:Cell Differentiation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006570:Heterochromatin / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014162:Transfection
D006570:Heterochromatin; D051783:Methyl-CpG-Binding Protein 2; D018008:Myogenin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006655:Histone Deacetylases