Transcription factor GLIS3: Critical roles in thyroid hormone biosynthesis, hypothyroidism, pancreatic beta cells and diabetes

Abstract

GLI-Similar 3 (GLIS3) is a member of the GLIS subfamily of Krüppel-like zinc finger transcription factors that functions as an activator or repressor of gene expression. Study of GLIS3-deficiency in mice and humans revealed that GLIS3 plays a critical role in the regulation of several biological processes and is implicated in the development of various diseases, including hypothyroidism and diabetes. This was supported by genome-wide association studies that identified significant associations of common variants in GLIS3 with increased risk of these pathologies. To obtain insights into the causal mechanisms underlying these diseases, it is imperative to understand the mechanisms by which this protein regulates the development of these pathologies. Recent studies of genes regulated by GLIS3 led to the identification of a number of target genes and have provided important molecular insights by which GLIS3 controls cellular processes. These studies revealed that GLIS3 is essential for thyroid hormone biosynthesis and identified a critical function for GLIS3 in the generation of pancreatic β cells and insulin gene transcription. These observations raised the possibility that the GLIS3 signaling pathway might provide a potential therapeutic target in the management of diabetes, hypothyroidism, and other diseases. To develop such strategies, it will be critical to understand the upstream signaling pathways that regulate the activity, expression and function of GLIS3. Here, we review the recent progress on the molecular mechanisms by which GLIS3 controls key functions in thyroid follicular and pancreatic β cells and how this causally relates to the development of hypothyroidism and diabetes.

Keywords: Diabetes; Gene transcription; Hypothyroidism; Insulin; Pancreatic β cells; Thyroid hormone biosynthesis.

Fig. 1.

Structure and function of human GLIS3 protein. The DNA binding domain (DBD) containing five C₂H₂ zinc finger motifs, the transactivation domain (TAD), and the highly conserved region (HCR) are indicated. The HCR contains a ciliary localization signal (CLS) that interacts with TNPO1 and is believed to facilitate GLIS3 entry into the primary cilium. GLIS3 transcriptional activity is regulated by multiple upstream pathways, including primary cilium-associated and primary cilium-independent pathways (Pathways 1 and 2, respectively), through the activation of different G protein-coupled receptors (GPCRs) by their respective external signals and downstream protein kinases.

Fig. 2.

GLIS3 plays a critical role in thyroid hormone biosynthesis. GLIS3 is expressed specifically in thyroid follicular cells where it directly regulates the expression of several thyroid hormone biosynthetic genes, including Nis, Pds, Mct8, and Tg. It also has a role in thyroid follicular cell proliferation and regulates several cell cycle genes, such as Cdca2, Ccnd2, and Cdc6. Low TH levels cause an increase in blood TSH, which by its interaction with TSHR leads to the subsequent activation of several kinase pathways through the TSHR coupled G proteins, G_s and G_q. It is believed that these kinases posttranslationally modify GLIS3 thereby significantly enhancing its transcriptional activity that results in strong induction of thyroid hormone biosynthetic genes. GLIS3 regulates transcription of these genes in coordination with other thyroid transcription factors, including PAX8 and NKX2.1.

Fig. 3.

Many of the GLIS3-associated SNPs related to diabetes and β cell dysfunction identified by GWAS located in intron 1 neighbor a region of β cell transcription factor binding. (A) Top panel shows the localization of several GLIS3-associated SNPs to intron 1 and 2. Below it are UCSC genome browser tracks of this region with the binding peaks of the indicated transcription factors as identified by ChIP-Seq with human pancreatic islets (Pasquali, et al., 2014). The y-axis indicates normalized read counts. (B) UCSC genome browser tracks of intron 1 and 2 of Glis3 showing the binding peaks of the indicated transcription factors as identified by ChIP-Seq with mouse pancreatic islets or β-cell lines (Ediger, et al., 2017; Gutierrez, et al., 2017; Hoffman, et al., 2010; Khoo, et al., 2012; Scoville, Lichti-Kaiser, Grimm, & Jetten, 2019; Taylor, Liu, & Sander, 2013; Tennant, et al., 2013). Details on data analysis can be found in Scoville et al. 2019. This comparison suggests a potential cis-acting regulatory role of this intronic region in the control of GLIS3 expression.

Fig. 4.

GLIS3 regulates pancreatic β cell gene transcription in coordination with other transcription factors. Top: Schematic of the expression of GLIS3 and other transcription factors during pancreas development. GLIS3 protein is first detectable in bipotent cells and remains expressed in endocrine progenitors and pancreatic β cells where it regulates the transcription of several genes. Lower panel: Comparison of genome browser tracks showing the binding peaks of the indicated transcription factor in the Ins2, Mafa, Slc2a2, and Slc30a8 genes as identified by ChIP-Seq of mouse pancreatic islets or β-cell lines (Ediger, et al., 2017; Gutierrez, et al., 2017; Hoffman, et al., 2010; Khoo, et al., 2012; Scoville, Lichti-Kaiser, Grimm, & Jetten, 2019; Taylor, Liu, & Sander, 2013; Tennant, et al., 2013). Many of the β cell transcription factors are bound in close proximity to one another on multiple critical genes suggesting they coordinate the transcriptional control of these genes. Mafa transcription is controlled by a previously identified upstream regulatory region within the Zc3h3 gene (Raum, et al., 2010). Details on data analysis can be found in Scoville et al. 2019. The y-axis indicates normalized read counts.