Glis3 regulates the expression of thyroid hormone synthetic genes in coordination with other thyroid transcription factors
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ABSTRACT:
ORGANISM(S): Mus musculus Rattus norvegicus
PROVIDER: GSE207777 | GEO | 2023/04/06
REPOSITORIES: GEO
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Project description:The serum hormone levels including T3 and T4 were dramatically decreased in Glis3-null mice due to reduced production of thyroid hormones in thyroid. Gene expression profile and EdU incorporation analysis between WT and Glis3-null mice showed that the cell proliferation was greatly reduced in Glis3-null thyroid. Goitergenic diet (low iodine diet; LID) dramatically enhanced serum TSH levels in both WT and Glis3-null mice, however thyroid goiter was observed in WT mice but not in Glis3-null mice. A subset of genes associated with thyroid hormone production including Pendrin (Slc26a4), Nis (Na+/I– symporter, Slc5a5), Duoxa2 (dualoxidase A2), Tpo (thyroperoxidase), and Dio1 (Deiodinase1) was significantly induced in WT but not in Glis3-null mice by LID feeding.
2017-11-06 | GSE86841 | GEO
Project description:Defined transcription factors can direct changes in programmed cell fate to give rise to various cell lineages, in contrast to the one-way street during development. Direct lineage conversions from fibroblasts occur in all the three germ layer derivatives- neurons, cardiomyocytes, and hepatocytes. However, direct reprogramming of thyroid lineages has not been accomplished yet. Previous studies demonstrated that exogenous Pax8 and Nkx2.1, which are indispensable for proper thyroid development, enable the pluripotent stem cell-derived definitive endoderm to differentiate into functional thyroid follicular cells. This raised the question whether a cocktail of thyroid development-related transcription factors can directly convert fibroblasts into thyroid follicular cells in vitro. In the current study, we found that induction of defined transcription factors is able to generate thyroid follicular cells from fibroblasts. Further, Pax8, Nkx2.1, Foxe1, Oct3/4, Sox2, Klf4, and c-Myc were sufficient to generate thyroglobulin (Tg)+/EpCAM+ colonies from mouse embryonic fibroblasts, and these colonies built three-dimensional (3D) follicular-like structures in matrigel-based 3D culture. These induced thyroid follicular-like cells, named iTF cells, were morphologically and transcriptionally similar to those of the adult thyroid. Finally, iTF cells were transplantable into the kidney capsule, and formed huge follicular structures in vivo as well. Our study therefore reveals that thyroid lineage can be directly derived from fibroblasts in a single step, and contributes to rapid translational research on human thyroid diseases such as hyperthyroidism.
2016-09-30 | GSE76266 | GEO
Project description:Deficiency in Krüppel-like zinc finger transcription factor, GLI-Similar 3 (GLIS3) in humans is associated with the development of congenital hypothyroidism. However, the functions of GLIS3 in the thyroid gland and by what mechanism GLIS3-dysfunction causes hypothyroidism are unknown. In this study, we demonstrate that GLIS3 acts downstream of thyroid stimulating hormone (TSH)/TSHR and is indispensable for TSH/TSHR-mediated induction of thyroid follicular cell proliferation and thyroid hormone biosynthesis. ChIP-Seq and promoter analysis revealed that GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, indicating that these genes are directly regulated by GLIS3. The repression of cell proliferation regulatory genes is due to the inhibition of TSH-mediated activation of the mTORC1/RPS6 pathway as well as direct transcriptional regulation of several cell division-related genes by GLIS3. Consequently, GLIS3-deficiency prevents the development of goiter as well as the induction of inflammatory and fibrotic genes during chronic elevation of circulating TSH. Our study identifies GLIS3 as a new and key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells, and uncovers a mechanism by which GLIS3-deficiency causes congenital hypothyroidism and prevents goiter development.
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Project description:The inhibitory effect of supra physiological iodide concentrations on thyroid hormone synthesis (Wolff-Chaikoff effect) and thyrocyte proliferation is largely know as iodine autoregulation. However, the molecular mechanisms by which iodide excess modulate thyroid functions remains unclear. In this work, we analyzed the rat follicular cell PCCl3 transcriptome profile under untreated and treated conditions with 10-3M sodium iodide (Na/I). Serial Analysis of Gene Expression revealed several transcripts differentially expressed in response to the iodide showing that excess iodide affects almost all aspects of thyroid cell function and differentiation acting on the iodine autoregulatory mechanism through a complex process. Keywords: comparative genomic analysis PCCl3 cells were cultured under untreated and treated conditions with 10-3M NaI during 24 hours
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Project description:The clinical importance of anterior foregut endoderm (AFE) derivatives, such as thyrocytes, has led to intense research efforts for their derivation through directed differentiation of pluripotent stem cells (PSCs). Here we identify transient overexpression of the transcription factor (TF) NKX2-1 as a powerful inductive signal for the robust derivation of thyrocyte-like cells from mouse PSC-derived AFE. This effect is highly developmental stage-specific and dependent upon FOXA2 expression levels and precise modulation of BMP and FGF signaling. The majority of the resulting cells express thyroid TFs (Nkx2-1, Pax8, Foxe1, Hhex) and thyroid hormone synthesis-related genes (Tg, Tpo, Nis, Iyd) at levels similar to adult mouse thyroid and give rise to functional follicle-like epithelial structures in Matrigel culture. Our findings demonstrate that NKX2-1 overexpression converts AFE to thyroid epithelium in a developmental time-sensitive manner and suggest a general methodology for manipulation of cell fate decisions of developmental intermediates.
2016-12-20 | GSE92572 | GEO
Project description:Comparison of cistromes from GLIS3 and HNF1b ChIP-Seq analysis using mouse kidney was performed to examine whether there was a significant overlap in target genes between GLIS3 and HNF1b.
2023-12-31 | GSE240072 | GEO
Project description:The thyroid maintains systemic homeostasis by regulating serum thyroid hormone concentrations. Here we report the establishment of adult stem cell-derived three-dimensional (3D) organoids representing murine and human thyroid follicular cells (TFCs). The TFC organoids (TFCO) harbour the complete machinery of hormone production as visualised by the presence of colloid in the lumen and by the presence of essential transporters and enzymes in the polarised epithelial cells that surround a central lumen. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1, while the thyroid hormone precursor thyroglobulin is expressed at comparable levels to tissue. Single cell RNA sequencing and transmission electron microscopy confirm that TFCOs phenocopy primary thyroid tissue. Thyroid hormones are readily detectable in conditioned medium of human TFCOs.
2021-12-06 | GSE183962 | GEO
Project description:The thyroid maintains systemic homeostasis by regulating serum thyroid hormone concentrations. Here we report the establishment of adult stem cell-derived three-dimensional (3D) organoids representing murine and human thyroid follicular cells (TFCs). The TFC organoids (TFCO) harbour the complete machinery of hormone production as visualised by the presence of colloid in the lumen and by the presence of essential transporters and enzymes in the polarised epithelial cells that surround a central lumen. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1, while the thyroid hormone precursor thyroglobulin is expressed at comparable levels to tissue. Single cell RNA sequencing and transmission electron microscopy confirm that TFCOs phenocopy primary thyroid tissue. Thyroid hormones are readily detectable in conditioned medium of human TFCOs.
2021-12-06 | GSE183961 | GEO
Project description:The thyroid maintains systemic homeostasis by regulating serum thyroid hormone concentrations. Here we report the establishment of adult stem cell-derived three-dimensional (3D) organoids representing murine and human thyroid follicular cells (TFCs). The TFC organoids (TFCO) harbour the complete machinery of hormone production as visualised by the presence of colloid in the lumen and by the presence of essential transporters and enzymes in the polarised epithelial cells that surround a central lumen. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1, while the thyroid hormone precursor thyroglobulin is expressed at comparable levels to tissue. Single cell RNA sequencing and transmission electron microscopy confirm that TFCOs phenocopy primary thyroid tissue. Thyroid hormones are readily detectable in conditioned medium of human TFCOs.
2021-12-06 | GSE183963 | GEO
Project description:Thyroid Transcription Factor-1 (TTF-1) is a key regulator of thyroid development and function. In order to identify the genes whose expression depends on TTF-1 transcriptional activity within the thyrocyte we analyzed the consequence of the functional inactivation of this factor in PCCl3 cells. The expression of a fusion protein composed of the DNA binding domain of TTF-1 and of the strong repressive domain of the Engrailed protein (Engr HD) resulted in a dramatic loss of epithelial cell morphology and in proliferation arrest. These changes were reversed when the inhibition of endogenous TTF-1 was relieved. No change was observed when a similar fusion protein containing point mutations abolishing DNA binding activity (Engr HDm) was produced in the cells.
2012-07-01 | GSE35623 | GEO