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| Status |
Public on Aug 30, 2017 |
| Title |
GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
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| Summary |
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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| Overall design |
Genome-wide mapping of endogenous GLIS3 in thyroid glands from GLIS3-EGFP mice fed a low-iodine diet (LID) for 2 weeks; RNA-Seq profiling of wild-type (WT) and Glis3KO thyroid glands from mice fed a LID.
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| Contributor(s) |
Kang HS, Kumar D, Liao G, Lichti-Kaiser K, Gerrish K, Liao X, Refetoff S, Jothi R, Jetten AM |
| Citation(s) |
36793061 |
| Submission date |
Aug 30, 2017 |
| Last update date |
May 31, 2023 |
| Contact name |
Raja Jothi |
| E-mail(s) |
jothi@mail.nih.gov
|
| Organization name |
National Institutes of Health
|
| Department |
National Institute of Environmental Health Sciences
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| Lab |
Systems Biology
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| Street address |
111 TW Alexander Drive; A314
|
| City |
RTP |
| State/province |
NC |
| ZIP/Postal code |
27709 |
| Country |
USA |
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| Platforms (2) |
| GPL16417 |
Illumina MiSeq (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA401666 |
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