GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

Kang, Hong Soon; Kumar, Dhirendra; Liao, Grace; Lichti-Kaiser, Kristin; Gerrish, Kevin; Liao, Xiao-Hui; Refetoff, Samuel; Jothi, Raja; Jetten, Anton M.

doi:10.1172/jci94417

Cited by 55 publications

(118 citation statements)

References 59 publications

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“…Although WNT signaling is known to play a critical role in A–P patterning, our understanding of the mechanisms that regulate WNT gene expression is still incomplete. We reported previously that GLIS3 regulates transcription by binding to GLIS binding sites (GLISBS) in the promoter region of target genes . Our ChIP‐Seq and functional studies show that GLIS3 binds to and transcriptionally activates several WNT genes, including WNT3A (Fig.…”

Section: Discussionmentioning

confidence: 58%

“…Comparison of genes targeted by GLIS3 with those induced or suppressed in G3‐hESCs(+) at 12 hours of NPC induction, revealed that approximately one‐third of the upregulated genes are GLIS3 targets ( p ‐value = 1.53E−13; hypergeometric test), whereas only ∼9% of the downregulated genes bind GLIS3 ( p ‐value = 0.99), consistent with GLIS3’s proposed role as a transcriptional activator . GO analysis of genes that were both targeted by GLIS3 and upregulated during NPC differentiation, revealed enrichment for genes associated with WNT signaling, embryonic development, and A–P axis specification (Fig.…”

Section: Resultsmentioning

confidence: 67%

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GLIS3 Transcriptionally Activates WNT Genes to Promote Differentiation of Human Embryonic Stem Cells into Posterior Neural Progenitors

et al. 2018

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Anterior–posterior (A–P) specification of the neural tube involves initial acquisition of anterior fate followed by the induction of posterior characteristics in the primitive anterior neuroectoderm. Several morphogens have been implicated in the regulation of A–P neural patterning; however, our understanding of the upstream regulators of these morphogens remains incomplete. Here, we show that the Krüppel‐like zinc finger transcription factor GLI‐Similar 3 (GLIS3) can direct differentiation of human embryonic stem cells (hESCs) into posterior neural progenitor cells in lieu of the default anterior pathway. Transcriptomic analyses reveal that this switch in cell fate is due to rapid activation of Wingless/Integrated (WNT) signaling pathway. Mechanistically, through genome‐wide RNA‐Seq, ChIP‐Seq, and functional analyses, we show that GLIS3 binds to and directly regulates the transcription of several WNT genes, including the strong posteriorizing factor WNT3A, and that inhibition of WNT signaling is sufficient to abrogate GLIS3‐induced posterior specification. Our findings suggest a potential role for GLIS3 in the regulation of A–P specification through direct transcriptional activation of WNT genes. Stem Cells 2018 Stem Cells 2019;37:202–215

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Section: Discussionmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 67%

GLIS3 Transcriptionally Activates WNT Genes to Promote Differentiation of Human Embryonic Stem Cells into Posterior Neural Progenitors

et al. 2018

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“…All five zinc finger motifs are required for optimal binding of GLIS proteins to GLISBS; loss of the first zinc finger has the least impact on this interaction. The in vivo consensus sequence of GLISBS derived from ChIP-Seq analysis exhibits high similarity with the GLISBS consensus sequence, (G/C)TGGGGG(A/C), identified by an in vitro screen [17, 23, 24]. Members of the closely-related GLI and ZIC families also bind G-rich DNA response elements similar to GLISBS and therefore might compete for the same binding site and interfere with each other’s action in cells in which they are co-expressed.…”

Section: Transcriptional Activity and Protein Interactionsmentioning

confidence: 99%

“…GLIS3 expression in the thyroid gland is restricted to the thyroid follicular cells [24]. The basic morphology of the thyroid gland and the expression of several genes critical for thyroid development, such as Pax8 , Ttf1 ( Nkx2.1 ), and Ttf2 ( FoxE1 ), are not greatly affected in PND7 Glis3-KO mice suggesting that abnormal thyroid gland development does not play a major role in the development of hypothyroidism in these Glis3-KO mice, but has a major function in regulating thyroid hormone biosynthesis and homeostasis (Fig.…”

Section: Molecular and Physiological Functions Of Glis1–3mentioning

confidence: 99%

“…Study of the subcellular localization of GLIS3 protein has indicated that it largely localizes to the nucleus in cells in vivo and when it is ectopically expressed in cultured cells [16, 23, 24, 119]. Immunohistochemistry using proximal tubule TKPTS cells ectopically expressing GLIS3-EGFP and kidney sections from transgenic mice expressing an GLIS3-EGFP fusion protein, showed that in addition to its nuclear localization, GLIS3 is also detectable in the tip of the primary cilium [49].…”

Section: Molecular and Physiological Functions Of Glis1–3mentioning

confidence: 99%

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GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

Jetten

2018

Cell. Mol. Life Sci.

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Krüppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-Similar 1–3 (GLIS1–3) constitute a subfamily of Krüppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1–3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases.

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GLIS rearrangements in thyroid nodules: A key to preoperative diagnosis of hyalinizing trabecular tumor

Nikiforova

Nikiforov

Ohori

2019

Cancer Cytopathology

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Hyalinizing trabecular tumor (HTT) is a rare thyroid neoplasm with peculiar morphologic features that overlap with those of papillary thyroid carcinoma (PTC). Specifically, the presence of enlarged oval nuclei, nuclear grooves, and intranuclear pseudoinclusions makes precise cytopathologic diagnosis challenging. If the cytopathologic diagnosis is suspicious for malignancy (Bethesda V) or is malignant (Bethesda VI), a total thyroidectomy, which would be considered an overtreatment, may follow. The recent discovery of the strong association between GLIS fusions and HTT sheds light on its pathogenesis and offers a pathway for its presurgical identification. Although the number of cases analyzed is limited, the recent landmark study shows that GLIS fusions are highly specific for HTT and that lobectomy is the likely appropriate surgical treatment, because these neoplasms, which lack invasion, are benign. For overall success, cytopathologic recognition of the subtle features is important to avoid false-positive diagnoses and directing potential HTT cases toward indeterminate cytopathologic diagnoses, which would trigger further molecular testing. Additional studies are needed to determine whether a malignant counterpart of GLIS fusion-positive HTT exists and if more conservative approaches may be taken.Hyalinizing trabecular tumor (HTT) is a rare type of thyroid neoplasm with peculiar morphology, and there is long-standing controversy with respect to its relationship to papillary carcinoma and clinical behavior. A recent study has described a unique molecular profile of these tumors, ending this controversy and paving the way for efficient preoperative detection of these tumors and guiding patients toward optimal management. 1

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GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

Cited by 55 publications

References 59 publications

GLIS3 Transcriptionally Activates WNT Genes to Promote Differentiation of Human Embryonic Stem Cells into Posterior Neural Progenitors

GLIS3 Transcriptionally Activates WNT Genes to Promote Differentiation of Human Embryonic Stem Cells into Posterior Neural Progenitors

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

GLIS rearrangements in thyroid nodules: A key to preoperative diagnosis of hyalinizing trabecular tumor

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