Neonatal thyroxine activation modifies epigenetic programming of the liver.

Area of Science:

• Endocrinology
• Epigenetics
• Developmental Biology

Background:

• Type 2 deiodinase (D2) in the neonatal liver is crucial for local thyroid hormone (T3) production.
• Thyroid hormone T3 influences gene expression and developmental processes.

Purpose of the Study:

• To investigate the long-term impact of neonatal T3 surge on hepatic gene expression.
• To elucidate the epigenetic mechanisms underlying T3-mediated permanent gene expression changes.

Main Methods:

• Liver-specific Dio2 inactivation (Alb-D2KO) in mice.
• Analysis of DNA methylation (H-sites) and chromatin accessibility (RCA).
• Chromosome conformation capture (Hi-C) to study 3D genome organization.

Main Results:

• Alb-D2KO mice showed transient H3K9me3 increase and permanent DNA methylation at 1,508 sites.
• Reduced chromatin accessibility and gene expression in 1,363 genes were observed.
• Hi-C data revealed physical interactions between promoter RCA and intergenic RCA sites.

Conclusions:

• Neonatal T3 surge permanently modifies hepatic gene expression through epigenetic mechanisms.
• D2-mediated T3 production during development establishes a long-lasting epigenetic landscape in the liver.
• These findings explain how local thyroid hormone action shapes future hepatic gene expression patterns.