Model-based analysis of matrix metalloproteinase expression under mechanical shear.
We report the development of a model-based analysis for identification of the role of transcription factor (TF) binding motifs. A nonlinear mathematical model was formulated to establish the quantitative relationship between the temporal expression profiles and the distribution of known TF binding motifs on regulatory DNA regions. In order to evaluate biological meaning of the nonlinear model, the role of TF binding motifs predicted by the model was examined by a promoter competition assay where specific TF binding motifs were inactivated by a transient transfer of the DNA fragments consisting of the TF binding motifs. Using the shear stress responses of a family of matrix metalloproteinases in human synovial cells as a model system, we showed that the nonlinear formulation was able to approximate the experimentally observed expression profile better than the linear formulation, and the stimulatory and inhibitory roles of TF binding motifs extracted from the model were validated by the competition assay. The results support that an integrated usage of the nonlinear model and the biochemical evaluation assay would contribute to identifying critical regulatory DNA elements in mechanical responses in connective tissue.
Sun
Hui Bin
HB
Biomedical Engineering Program, Department of Anatomy and Cell Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA.
Liu
Yunlong
Y
Qian
Lei
L
Yokota
Hiroki
H
D020816:Amino Acid Motifs / Q000235:genetics / Q000502:physiology; D003198:Computer Simulation; D004247:DNA / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016014:Linear Models; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D008957:Models, Genetic; D017711:Nonlinear Dynamics; D010812:Physical Stimulation / Q000379:methods; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D017422:Sequence Analysis, DNA; D033081:Shear Strength; D013314:Stress, Mechanical; D013583:Synovial Membrane / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D014157:Transcription Factors; D004247:DNA; D020782:Matrix Metalloproteinases