# TET1 loss propels the development of hyperthyroidism by remodeling histone modifications of PAX8 promoter

## TL;DR

TET1, a DNA-modifying protein, suppresses thyroid function by altering gene activity, and its absence leads to hyperthyroidism in mice.

## Contribution

The study reveals a novel mechanism by which TET1 regulates thyroid function through histone modification of the PAX8 promoter.

## Key findings

- Thyroid-specific TET1 knockout mice developed hyperthyroidism with hypermetabolic symptoms.
- TET1 suppresses thyroid hormone-related genes by reducing histone acetylation at the PAX8 promoter.
- Elevated miR-29c-3p in exosomes may contribute to hyperthyroidism by targeting TET1.

## Abstract

Ten eleven translocation 1 (TET1) is a 5-methylcytosine dioxygenase, and its altered DNA demethylation has been implicated in human diseases. However, its role in regulating thyroid function remains totally unknown. Here we first generated thyroid-specific Tet1 knockout combined with thyroid-specific BrafV600E transgenic mouse model (Thy-BrafV600E; Tet1−/−) and their control mice (Thy-BrafV600E; Tet1+/+). The latter developed severe hypothyroidism and lost reproductive ability owing to structural damages of thyroid gland, while thyroid-specific Tet1 knockout effectively restored thyroid structure and function of Thy-BrafV600E; Tet1+/+ mice and their reproductive ability. In addition, we also established thyroid-specific Tet1 knockout mouse model (Thy-Tet1−/−) and demonstrated that these mice could develop hyperthyroidism with systemic hypermetabolic symptoms such as weight loss, increased heart rate and elevated systolic blood pressure, further supporting the inhibitory effect of TET1 on thyroid function. Transcriptomic sequencing revealed that key genes related to metabolism and synthesis of thyroid hormones such as PAX8, SLC5A5 and TPO were significantly upregulated in Thy-Tet1−/− mice. Mechanistically, TET1 recruits HDAC1 to reduce the levels of H3K27Ac and H3K9Ac in the PAX8 promoter, thereby inhibiting the expression of itself and its downstream targets NIS and TPO. Further studies showed that elevated miR-29c-3p in serum exosomes enhanced thyroid function by targeting TET1, which may be one of the causes of hyperthyroidism. Thus, this study uncovers a new mechanism by which TET1 suppresses thyroid function, providing a new perspective to explore the pathogenesis of hyperthyroidism.

Hyperthyroidism is a condition in which the thyroid gland produces too many hormones, leading to symptoms such as weight loss and irritability. Here scientists are exploring the role of a protein called TET1 in thyroid function. TET1 is known for its role in modifying DNA, which can affect how genes are turned on or off. In this study, researchers investigated whether TET1 influences thyroid activity. They used mice that were genetically modified to lack TET1 specifically in their thyroid glands. These mice showed signs of hyperthyroidism such as increased thyroid hormone levels and faster metabolism. The researchers found that TET1 normally helps suppress the activity of certain genes involved in thyroid hormone production by interacting with other proteins that modify DNA structure. This study suggests that TET1 plays a crucial role in regulating thyroid function and that its absence can lead to hyperthyroidism.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.