Uncovering a dynamic model of thyroid hormone receptor function How T3 regulates gene transcription via TRs has been understood by the decade's old bimodal switch model, TRs bind stably to chromatin at cognate recognition elements and serve as a scaffold for super-complexes of cofactors which activate or repress transcription. In the absence of T3, these scaffolds attract repressive cofactors; upon activation by T3, repressive factors are displaced, new activating cofactors are recruited, and target genes are induced. Combining genome-wide ChIP-seq analysis for receptor binding with Dnase-seq hypersensitivity (DHS) assays to monitor open and closed chromatin states, we observed many de novo genome binding events for the receptor. That is, rather than existing as a stable, chromatin-bound repressive factor, the receptor often moved actively to TREs (thyroid response elements) in a hormone-dependent fashion. Furthermore, the receptor often created localized open chromatin structures at the binding sites. Moreover, a technique termed Digital Genome Footprinting allowed us to monitor the stability of bound TRs. A bound factor should protect hypersensitive regions of the DNA from degradation by DNase, resulting in a predictable footprint. Strikingly, none of the TRs binding sites, either activating or repressing, showed any evidence of a corresponding footprint. Although no footprints were observed, TR binding sites were universally marked by specific cleavage signatures, which correspond precisely to the ThR DNA binding motifs. These nuclease cleavage patterns result from the DNA structure itself, and in fact represent the chemical structure that the receptor recognizes. The combined results support an altered view of TR function. In the dynamic model, the receptor exchanges rapidly and continuously with response elements in chromatin. In the absence of ligand, the receptor recruits corepressors to binding elements, but these complexes are not statically bound to chromatin. Upon activation by the hormone, the receptor recruits coactivators rather than corepressors, thus inducing target genes, but the mode of action remains highly dynamic, with receptor exchanging rapidly with binding elements. For steroid receptors, this mode of action has recently been termed dynamic assisted loading and recent advances in single molecule tracking in live cells place the residence times in the range of 5-10 seconds per binding event. Our studies indicate that TR behave as highly mobile factors with the ability to initiate the chromatin transitions necessary for cofactor recruitment and enhancer action. This new model of T3 action represents a significant step toward a better understanding of mechanisms of gene regulation by this important hormone. Importantly, the present work has facilitated the studies for gaining molecular insights into the basis of TR mutations in disease.