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

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 Braf^V600E transgenic mouse model (Thy-Braf^V600E; Tet1^-/-) and their control mice (Thy-Braf^V600E; 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-Braf^V600E; 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.