Multi-omics investigation of thyroid development and dysfunction in down syndrome.

Area of Science:

• Endocrinology
• Genetics
• Developmental Biology

Background:

• Down syndrome (DS) is associated with a high prevalence of congenital non-autoimmune thyroid dysfunction, often presenting as elevated thyroid stimulating hormone (TSH).
• The precise pathophysiological mechanisms driving thyroid dysfunction in DS remain unclear, despite evidence suggesting a developmental origin.
• Understanding these mechanisms is crucial for managing thyroid health in individuals with DS.

Purpose of the Study:

• To investigate the molecular and developmental factors contributing to thyroid dysfunction in Down syndrome.
• To identify specific genetic and epigenetic alterations in fetal thyroid tissue associated with DS.
• To elucidate the underlying mechanisms of congenital thyroid dysfunction in DS.

Main Methods:

• Analysis of fetal thyroid tissue from individuals with DS (n=4) and controls (n=5) using histology.
• Genome-wide gene expression profiling via bulk RNA sequencing (RNA-seq).
• DNA methylation (DNAm) profiling and integration with RNA-seq data.

Main Results:

• Histological examination showed underdeveloped DS fetal thyroid tissue with smaller, heterogeneous follicles.
• RNA-seq identified 1035 differentially expressed genes (DEGs), including downregulated thyroid-specific genes (FOXE1, IYD, DIO2).
• DNA methylation analysis revealed 266 differentially methylated regions (DMRs), with integrated analysis suggesting cis-regulatory DNAm effects on gene expression.

Conclusions:

• Congenital thyroid dysfunction in DS is a distinct condition characterized by impaired thyroid development and altered gene regulation.
• Genome-wide molecular changes, including gene dosage effects and epigenetic disturbances from trisomy 21, underlie this dysfunction.
• These findings highlight a DS-specific molecular signature impacting thyroid development and function.