Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

Yamauchi, I.; Sugawa, T.; Hakata, T.; Yoshizawa, A.; Kita, T.; Kishimoto, Y.; Kimura, S.; Kosugi, D.; Fujita, H.; Okamoto, K.; Ueda, Y.; Fujii, T.; Taura, D.; Sakane, Y.; Yasoda, A.; Inagaki, N.

doi:10.1101/2023.10.27.564354

bioRxiv · 10.1101/2023.10.27.564354

Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

Yamauchi, I.·Sugawa, T.·Hakata, T.·Yoshizawa, A.·Kita, T.·Kishimoto, Y.·Kimura, S.·Kosugi, D.·Fujita, H.·Okamoto, K.·Ueda, Y.·Fujii, T.·Taura, D.·Sakane, Y.·Yasoda, A.·Inagaki, N.

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Abstract

Hyperthyroidism is a condition with excessive thyroid hormone secretion. Activation of thyroid stimulating hormone receptor (TSHR) fundamentally leads to hyperthyroidism. The details of TSHR signaling remain to be elucidated. We conducted transcriptome analyses for hyperthyroid mice that we generated by overexpressing TSH. TSH overexpression via hydrodynamic gene delivery with pLIVE-TSHB and pLIVE-CGA vectors consistently caused hyperthyroidism and goiters for at least 4 weeks in C57BL/6J mice. RNA sequencing analysis of their thyroid glands revealed that thiamazole slightly changed the thyroid transcriptome, which reinforces a conventional theory that thiamazole decreases thyroid hormone secretion via inhibition of thyroid peroxidase activity. Meanwhile, TSH overexpression drastically changed the thyroid transcriptome. In particular, enrichment analyses identified the cell cycle, phosphatidylinositol-3 kinase/Akt pathway, and Ras-related protein 1 pathway as possibly associated with goiter development. Regarding the role of TSHR signaling in hyperthyroidism, it is noteworthy that Slc26a4 was exclusively upregulated among genes crucial to thyroid hormone secretion at both 1 and 4 weeks after hydrodynamic gene delivery. To verify the relationship between this upregulation and hyperthyroidism, we overexpressed TSH in Slc26a4 knockout mice. TSH overexpression caused hyperthyroidism in Slc26a4 knockout mice, equivalent to that in control mice. To summarize, we analyzed hyperthyroid mice generated by TSH overexpression. We did not observe significant changes in known genes and pathways involved in thyroid hormone secretion. Thus, our datasets might include candidate genes that have not yet been identified as regulators of thyroid function. Our transcriptome datasets regarding hyperthyroidism can contribute to future research on TSHR signaling.

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Yamauchi, I., Sugawa, T., Hakata, T., Yoshizawa, A., Kita, T., Kishimoto, Y., Kimura, S., Kosugi, D., Fujita, H., Okamoto, K., Ueda, Y., Fujii, T., Taura, D., Sakane, Y., Yasoda, A., Inagaki, N.. 2023-10-27. Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone. https://doi.org/10.1101/2023.10.27.564354

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