ESPE Yearbook of Paediatric Endocrinology

Genes Dev. 2021;35(5–6):367–378. doi: 10.1101/gad.345686.120.

The longstanding concept of thyroid hormone (TH) action is summarized as the canonical switch model. This study adds important aspects of TH action to our current understanding, modifying this longstanding switch model to a “shift” model.

According to the current concept, TH dependent gene expression is upregulated upon binding of TH to nuclear thyroid hormone receptors (TR) which are bound to DNA at TR binding sites (TRBS). TH binding to TRs at TRBS induces a switch between repressed and activated states by corepressor release and coactivator recruitment resulting in activated gene expression [1,2]. A recent study presented in the 2020 Yearbook chapter suggested that this model may explain only the upregulation of a subset of TH regulated genes [3].

Shabtai et al. add more evidence to this more differentiated view of thyroid hormone action studying thyroid hormone action in the murine liver. To overcome technical limitations of earlier studies due to the low physiological expression level of TRs, they developed a specific in vivo mouse model with epitope-tagged TRbeta1 protein to allow efficient and specific chromatin immunoprecipitation experiments under hypothyroid and hyperthyroid conditions. First, the authors showed for the first time, that not only transcriptional activation of TH target genes but also transcriptional repression was dependent on direct binding of TH to TRBS. Second, the authors quantified corepressor and coactivator levels at enhancers of genes upregulated or downregulated by TH. They observed a shift of corepressors and coactivators upon TH action rather than a complete switch from repressive to activating state.

Reference: 1. Hörlein AJ, Näär AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Söderström M, Glass CK, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature. 1995;377(6548):397–404. doi: 10.1038/377397a0.2. Ishizuka T, Lazar MA. The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor. Mol Cell Biol. 2003;23:5122–31. doi: 10.1128/MCB.23.15.5122-5131.20033. Præstholm SM, Siersbæk MS, Nielsen R, Zhu X, Hollenberg AN, Cheng SY, Grøntved L. Multiple mechanisms regulate H3 acetylation of enhancers in response to thyroid hormone. PLoS Genet. 2020 May 26;16(5):e1008770. doi: 10.1371/journal.pgen.1008770. eCollection 2020 May.