DNA architecture plays a key role in determining spatial and temporal patterns of gene expression. This architecture encompasses both the nucleotide sequence (i.e., the information content) and the physical state of the DNA such as its spatial organization and mechanical properties. We study several regulatory motifs in E. coli using a three pronged approach: theoretical modeling, in vitro single molecule experiments, and in vivo single cell experiments. Through systematic experimentation we show that we can account for the effect of varying the different relevant "knobs" governing a repression regulatory motif such as the concentration of transcription factor and the strength of their binding to DNA. The result is a framework that predicts the regulatory outcome of any mutant of this regulatory architecture, which we show can be tested in a variety of different ways. We also present our recent experimental efforts aimed at dissecting repression by DNA looping and the sequence-dependent flexibility associated with the mechanical code of the DNA.