Physiologic Significance of Epigenetic Regulation of Thyroid Hormone Target Gene Expression

Abstract

Background: In previous publications, we have reported our findings demonstrating that exposure to high maternal levels of thyroid hormones (TH) has life-long effects on the wild-type (WT, without THRB mutation) progeny of mothers with resistance to thyroid hormone beta (RTHβ). The mechanism of this epigenetic effect remains unclear.

Objectives: We reviewed the mechanisms involved in the epigenetic regulation of TH target genes and understand how they may explain the reduced sensitivity to TH in the WT progeny of RTHβ mothers.

Methods: The availability of a large, formerly genotyped Azorean population with many individuals harboring the THRB mutation, R243Q, provided us a model to study the influence of fetal exposure to high maternal TH levels.

Results: The thyroid-stimulating hormone (TSH) response in WT adults was less suppressible following the administration of L-triiodothyronine (L-T₃). This finding suggests reduced sensitivity to TH that is induced by an epigenetic mechanism resulting from exposure to high maternal levels of TH during pregnancy. The persistence of this effect across 3 generations of WT subjects favors transgenerational epigenetic inheritance. Based on preliminary studies in mice, we identified the naturally imprinted gene encoding deiodinase type 3, i.e., DIO3, as a possible mediator of this epigenetic effect through increased inactivation of TH.

Conclusion: Increased D3 expression and consequently increased T₃ degradation appear to be responsible for the reduced sensitivity of the anterior pituitary to administered L-T₃. The imprinted DIO3 gene may be a candidate gene that mediates the epigenetic effect induced by exposure to high maternal levels of TH. However, we cannot exclude the role of other TH-responsive genes.

Keywords: Deiodinase type 3; Epigenetic regulation; Resistance to thyroid hormone beta; Transgenerational inheritance.

Fig. 1

In the absence of T₃, thyroid receptors (TR) form heterodimers with retinoic X receptor (RXR) and the complexes bind to the thyroid hormone (TH) response elements (TRE) in target genes to repress their expression. Binding of T₃ to TR releases CoR (corepressors) and recruits coactivator complexes containing histone acetyltransferases (HAT). Acetyl groups from acetyl-CoA are added by HAT onto the lysine residues of the histone tails, resulting in active chromatin, while the removal of acetyl residues by histone deacetylases (HDAC) results in the repression of chromatin. T₃ regulates the levels of microRNA that block mRNA, leading to gene silencing. Methylation of DNA and histone is mostly associated with gene repression.

Fig. 2

Reduced sensitivity to thyroid hormones (TH) is an epigenetic phenomenon transmitted along male line. F0 is the pregnant RTHβ mother. The wild-type (WT) embryo (F1) is directly exposed to high maternal levels of TH. This is also true for the developing germ cell lines in the testicles (male transmission) which may also affect the F2 generation (i.e., the grandmother's influence). The F3 generation is therefore the first generation that has not been exposed to high levels of TH.

Fig. 3

The imprinting control region of the gene encoding deiodinase type 3 (DIO3) contains multiple DNA sequences called insulators, which bind the transcriptional repressor CCCTC-binding factor (CTCF). The insulators are methylated when paternally inherited and unmethylated when derived from the mother. CTCF can only bind to unmethylated sequences of maternal origin. Binding of CTCF to insulators leads to chromatin loop formation in a manner that blocks communication between the enhancer and the promoter of DIO3, repressing its expression.