Thyroidal Transcriptomic Profiles of Pathoadaptive Responses to Congenital Hypothyroidism in XB130 Knockout Mice

Abstract

Congenital hypothyroidism is a genetic condition in which the thyroid gland fails to produce sufficient thyroid hormone (TH), resulting in metabolic dysfunction and growth retardation. Xb130−/− mice exhibit perturbations of thyrocyte cytoskeleton and polarity, and develop postnatal transient growth retardation due to congenital hypothyroidism, leading ultimately to multinodular goiter. To determine the underlying mechanisms, we performed transcriptomic analyses on thyroid glands of mice at three age points: week 2 (W2, before visible growth retardation), W4 (at the nadir of growth); and W12 (immediately before full growth recovery). Using gene set enrichment analysis, we compared a defined set of thyroidal genes between Xb130+/+ and Xb130−/− mice to identify differentially enriched gene clusters. At the earliest postnatal stage (W2), the thyroid glands of Xb130−/− mice exhibited significantly downregulated gene clusters related to cellular metabolism, which continued to W4. Additionally, mutant thyroids at W4 and W12 showed upregulated gene clusters related to extracellular matrix, angiogenesis, and cell proliferation. At W12, despite nearly normal levels of serum TH and TSH and body size, a significantly large number of gene clusters related to inflammatory response were upregulated. Early postnatal TH deficiency may suppress cellular metabolism within the thyroid gland itself. Upregulation of genes related to extracellular matrix and angiogenesis may promote subsequent thyroid growth. Chronic inflammatory responses may contribute to the pathogenesis of multinodular goiter in later life. Some of the pathoadaptive responses of Xb130−/− mice may overlap with those from other mutations causing congenital hypothyroidism.

Thyroid hormone protects human lung epithelial cells from cold preservation and warm reperfusion-induced injury

“…Thus, the identification of therapeutic targets of IR injury for pharmacological intervention is a major research goal in transplantation medicine. In the present study, we found that the transcriptomic profile of human lung epithelial cells exposed to simulated transplant conditions had a signature profile like those found in clinical human lung transplants [13] and in the thyroid glands of mice with congenital hypothyroidism [18]. This prompted us to investigate whether incorporating THs into the standard clinical lung preservation solution could protect against IR injury.…”

“…A recent bioinformatics study showed that in the thyroid tissue of mice with congenital hypothyroidism, there is a downregulation of gene clusters related to cellular metabolism, followed by an up-regulation of genes related to inflammation [18]. THs are critical for many essential cellular functions, especially metabolism [19] and protein synthesis [20].…”