Thyroid hormone receptor actions on transcription in amphibia: The roles of histone modification and chromatin disruption

Thyroid hormone (T3) affects numerous biological processes in vertebrates and thyroid diseases are arguably the most prevalent group of metabolic disorders in the world [1-3]. In the adult mammals such as humans, T3 deficiency leads to reduced metabolic rate while both hyperthyroidism and hypothyroidism result in abnormal function of diverse organs and tissues [4-6].T3 plays a critical role for vertebrate development. T3 deficiency during human development leads to a number of developmental defects, including the formation of a goiter, i.e., a lump in the neck due to enlarged thyroid gland, and cretinism, which is manifested with severe mental deficiency and short stature [7,8]. Similar requirement for T3 is also observed in other vertebrates. The most dramatic T3-regulated developmental process is anuran metamorphosis, when an aquatic tadpole is transformed into a terrestrial frog, as first demonstrated a century ago [9-11]. This process resembles the postembryonic, or perinatal development in mammals when plasma T3 levels also peak [12].T3 can exert its effects at both the genomic level through nuclear T3 receptors (TRs) and the non-genomic levels. The non-genomic effects of T3 involve the binding of T3 to diverse cellular proteins. Among them include the cell surface integrin αVβ3, better known as a receptor for the extracellular matrix, and a number of cytosolic proteins, which have additional, often enzymatic functions [13-19]. In addition, while TRs are predominantly localized in the nucleus even in the absence of T3, some are present in the cytoplasm. Interestingly, cytosolic TRβ can form a complex with the signaling kinase MAPK, which may be responsible for the rapid activation of MAPK by T3 [19], and unliganded TRβ can interact with phosphatidylinosital 3 kinase (PI3K) to activate this signaling pathway [20,21], suggesting that cytoplasmic TR may mediate some non-genomic effect of T3.The genomic action of T3, i.e., transcriptional regulation through TR, is