Tissue- and gene-specific recruitment of steroid receptor coactivator-3 by thyroid hormone receptor during...

Area of Science:

• Developmental Biology
• Molecular Endocrinology
• Gene Regulation

Background:

• Nuclear hormone receptors, like thyroid hormone receptor (TR), regulate gene expression.
• Coactivators are essential for receptor function, but their in vivo developmental roles are less understood.
• Amphibian metamorphosis provides a powerful model to study TR action during development.

Purpose of the Study:

• To investigate the in vivo role of steroid receptor coactivator 3 (SRC3) in thyroid hormone receptor (TR)-mediated gene activation during amphibian metamorphosis.
• To determine if SRC3 is recruited to endogenous TR target genes in a tissue-specific manner.
• To assess the functional significance of SRC3 recruitment during metamorphosis.

Main Methods:

• Gene expression analysis of SRC3 in tadpole organs during natural and induced metamorphosis.
• Chromatin immunoprecipitation (ChIP) assays to detect in vivo recruitment of SRC3 to TR target genes.
• Utilizing transgenic tadpoles expressing a dominant-negative SRC3 (F-dnSRC3) to block coactivator function.

Main Results:

• SRC3 expression was detected in all tadpole organs and upregulated in the tail and intestine during metamorphosis.
• SRC3 recruitment to TR target genes was gene- and tissue-dependent, with variable T3-dependency observed in different tissues.
• Dominant-negative SRC3 blocked endogenous coactivator recruitment and histone acetylation at target gene promoters in a T3-dependent manner.

Conclusions:

• SRC3 is recruited by TR to target genes in a gene- and tissue-specific manner during amphibian development.
• SRC3 plays a crucial role in mediating thyroid hormone signaling during metamorphosis.
• The findings highlight the complex regulation of coactivator function in vivo during developmental processes.