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In vivo Characterization of Endocrine Disrupting Chemical Effects via Thyroid Hormone Action Indicator Mouse
Published on: October 6, 2023
Gene specific actions of thyroid hormone receptor subtypes
Jean Z Lin1, Douglas H Sieglaff, Chaoshen Yuan
1Genomic Medicine, The Methodist Hospital Research Institute, Houston, Texas, United States of America.
Plos One
|January 10, 2013
Summary
Thyroid hormone receptors (TRs) α and β show subtle differences in gene regulation. While not completely specific, TR subtypes exhibit distinct effects on gene response kinetics and magnitude, impacting TH physiology and drug development.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Two homologous thyroid hormone receptors (TRs), TRα and TRβ, are nuclear hormone receptors (NRs).
- Initial studies suggested overlapping functions of TR subtypes in gene regulation.
- Related NRs often regulate distinct gene sets, prompting investigation into TR subtype specificity.
Purpose of the Study:
- To determine the extent of differential target gene regulation by TRα and TRβ.
- To compare the effects of TRα and TRβ on gene expression in different cellular contexts.
- To identify TR subtype-specific effects on thyroid hormone (T3) response.
Main Methods:
- Comparing effects of stably expressed exogenous TRα and TRβ in HepG2 and HeLa cells.
- Assessing gene responses to unliganded TRs and T3.
- Utilizing cycloheximide (CHX) treatment to identify direct TR target genes.
Main Results:
- Hundreds of genes responded to T3 or unliganded TRs, but no completely TR subtype-specific gene regulation was found.
- TR subtypes demonstrated differential effects on global T3 response kinetics in HepG2 cells.
- Specific genes showed variations in response magnitude, regulation patterns, and T3 dose-response curves between TR subtypes.
- CHX treatment confirmed direct TR target genes exhibit differential effects.
Conclusions:
- TRα and TRβ actions are not identical, with subtype-specific effects observed at the individual gene level.
- Gene-selective mechanisms of TR action highlight functional differences between TR subtypes.
- Differential TR actions may influence physiological and pharmacological responses to thyroid hormones and selective TR modulators (STRMs).
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