Abstract
Thyroid hormone (T3) plays diverse roles in adult organ function and during vertebrate development. The most important stage of mammalian development affected by T3 is the perinatal period when plasma T3 level peaks. Amphibian metamorphosis resembles this mammalian postembryonic period and is absolutely dependent on T3. The ability to easily manipulate this process makes it an ideal model to study the molecular mechanisms governing T3 action during vertebrate development. T3 functions mostly by regulating gene expression through T3 receptors (TRs). Studies in vitro, in cell cultures and reconstituted frog oocyte transcription system have revealed that TRs can both activate and repress gene transcription in a T3-dependent manner and involve chromatin disruption and histone modifications. These changes are accompanied by the recruitment of diverse cofactor complexes. More recently, genetic studies in mouse and frog have provided strong evidence for a role of cofactor complexes in T3 signaling in vivo. Molecular studies on amphibian metamorphosis have also revealed that developmental gene regulation by T3 involves histone modifications and the disruption of chromatin structure at the target genes as evidenced by the loss of core histones, arguing that chromatin remodeling is an important mechanism for gene activation by liganded TR during vertebrate development.
Highlights
Thyroid hormone (T3) affects numerous biological processes in vertebrates and thyroid diseases are arguably the most prevalent group of metabolic disorders in the world [1,2,3]
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 T3 receptors (TRs) may mediate some nongenomic effect of T3
By using Chromatin immunoprecipitation (ChIP) assay with antibodies again core histones H2B and H3, we have recently shown that during either T3-induced or natural metamorphosis, T3 induces the removal of core histones from the TRE regions of T3 response genes, including TRβ, in the Xenopus tropicalis intestine, accompanying increased TR binding and recruitment of RNA polymerase II (Figure 3A) [113]
Summary
Thyroid hormone (T3) affects numerous biological processes in vertebrates and thyroid diseases are arguably the most prevalent group of metabolic disorders in the world [1,2,3]. By using ChIP assay with antibodies again core histones H2B and H3, we have recently shown that during either T3-induced or natural metamorphosis, T3 induces the removal of core histones from the TRE regions of T3 response genes, including TRβ, in the Xenopus tropicalis intestine, accompanying increased TR binding and recruitment of RNA polymerase II (Figure 3A) [113] This finding suggests local removal of nucleosomes by liganded TR, consistent with the observations in the frog oocyte transcription system. T3 induces changes in histone modifications at target genes presumably by recruiting different cofactor complexes via TRs. ChIP assays have shown that during Xenopus laevis or tropicalis metamorphosis, increased histone acetylation correlates with the activation of T3 target genes (Figure 3B), the release of corepressors and the recruitment of coactivators [31,77,86,87,88,89,100,113,117,120]. T3 activates the Dot1L gene, and Dot1L in turn feeds back positively on liganded TR function during metamorphosis by methylating H3K79 at T3 target genes
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