Abstract
Thyroid hormones mediate a remarkable range of functions in many tissues and organ systems through the thyroid hormone receptors—THRA and THRB. Tissues and organs are composed of heterogeneous cells of different cell types. These different cell types have varying receptor expression abilities, which lead to variable responses in thyroid hormone regulation. The tissue-specific Thra and Thrb gene expression patterns help us understand the action of thyroid hormones at the tissue level. However, the situation becomes complicated if we wish to focus on tissues more closely to trace the responsive cells, which is a vital step in the process of understanding the molecular mechanism of diseases related to thyroid hormone regulation. Single-cell RNA sequencing technology is a powerful tool used to profile gene expression programs in individual cells. The Tabula Muris Consortium generates a single-cell transcriptomic atlas across the life span of Mus musculus that includes data from 23 tissues and organs. It provides an unprecedented opportunity to understand thyroid hormone regulation at the cell type resolution. We demonstrated the approaches that allow application of the single-cell RNA-Seq data generated by the Tabula Muris Consortium to trace responsive cells in tissues. First, employing the single-cell RNA-Seq data, we calculated the ability of different cell types to express Thra and Thrb, which direct us to the cell types sensitive to thyroid hormone regulation in tissues and organs. Next, using a cell clustering algorithm, we explored the subtypes with low Thra or Thrb expression within the different cell types and identified the potentially responsive cell subtypes. Finally, in the liver tissue treated with thyroid hormones, using the single-cell RNA-Seq data, we successfully traced the responsive cell types. We acknowledge that the computational predictions reported here need to be further validated using wet-lab experiments. However, we believe our results provide powerful information and will be beneficial for wet lab researchers.
Highlights
Thyroid hormones mediate a remarkable range of functions in many tissues and organ systems [1]
The mechanism by which cell types respond to thyroid hormone regulation, and which are the primary responsive cells is a critical question in understanding the molecular mechanism of thyroid hormone regulation diseases
We analyzed the cell types comprising the liver and found fibroblasts had the highest levels of Thra expression while hepatocytes had the highest Thrb expression, which suggests they are potentially the most sensitive cell type for thyroid hormone regulation through Thra and Thrb
Summary
Thyroid hormones mediate a remarkable range of functions in many tissues and organ systems [1]. There are two main classes of thyroid hormone receptors: alpha, which is encoded by THRA and beta, which is encoded by THRB [3]. The ability to express either of the receptor genes in a cell provides a means of conferring a specific biological response towards thyroid hormone regulation. Over the last three decades, numerous studies related to the expression of thyroid hormone receptor genes have been published. The expression of Thra and Thrb has been thoroughly investigated; Flamant and Gauthier provided a comprehensive review of this topic [2]. Mutations in the thyroid hormone receptor gene are associated with thyroid hormone resistance [8], which has resulted in substantial work in laboratories across the world to investigate their expression in multiple tissues. THRA/Thra is predominantly expressed in the heart and brain, whereas THRB/Thrb is largely expressed in the brain, fat, kidney, and liver
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