GLIS1-3: Links to Primary Cilium, Reprogramming, Stem Cell Renewal, and Disease

Abstract

The GLI-Similar 1-3 (GLIS1-3) genes, in addition to encoding GLIS1-3 Krüppel-like zinc finger transcription factors, also generate circular GLIS (circGLIS) RNAs. GLIS1-3 regulate gene transcription by binding to GLIS binding sites in target genes, whereas circGLIS RNAs largely act as miRNA sponges. GLIS1-3 play a critical role in the regulation of many biological processes and have been implicated in various pathologies. GLIS protein activities appear to be regulated by primary cilium-dependent and -independent signaling pathways that via post-translational modifications may cause changes in the subcellular localization, proteolytic processing, and protein interactions. These modifications can affect the transcriptional activity of GLIS proteins and, consequently, the biological functions they regulate as well as their roles in disease. Recent studies have implicated GLIS1-3 proteins and circGLIS RNAs in the regulation of stemness, self-renewal, epithelial-mesenchymal transition (EMT), cell reprogramming, lineage determination, and differentiation. These biological processes are interconnected and play a critical role in embryonic development, tissue homeostasis, and cell plasticity. Dysregulation of these processes are part of many pathologies. This review provides an update on our current knowledge of the roles GLIS proteins and circGLIS RNAs in the control of these biological processes in relation to their regulation of normal physiological functions and disease.

Developmental regulators moonlighting as transposons defense factors

“…GLIS Family Zinc Finger 3 (GLIS3) is a nuclear protein harboring 5 C2H2‐type zinc finger domains that serve as both a transcriptional activator and repressor 79,80 . In the male reproductive tract, GLIS3 is transiently expressed in PGCs and then re‐expressed in ProSG.…”

“…GLIS Family Zinc Finger 3 (GLIS3) is a nuclear protein harboring 5 C2H2-type zinc finger domains that serve as both a transcriptional activator and repressor. 79,80 In the male reproductive tract, GLIS3 is transiently expressed in PGCs and then re-expressed in ProSG. GLIS3 expression persists until the undifferentiated SG stage and then is downregulated before the differentiating SG stage postnatally.…”

GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression

“…We provide evidence showing that TSH and activation of protein kinase A (PKA) enhance the transcriptional activity of GLIS3. We propose that the induction of several TH biosynthesis-related genes by TSH, particularly in mice fed a LID, is in part related to the increase in GLIS3 transcriptional activity [ 14 , 15 , 35 ]. Although, TSH also induces the expression of cell cycle-regulatory genes, our study shows that, unlike TH biosynthesis-related genes, they are not directly regulated by GLIS3 but indirectly through changes in gene expression in other GLIS3 target tissues.…”

Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice

“…These observations indicate that the inhibition of proliferation and cell cycle-related genes in ubiquitous Glis3 KO thyroid is related to changes in gene expression in other GLIS3 target tissues that indirectly affect thyroid follicular cell proliferation. Studies showing that GLIS3 is particularly critical for the transcriptional regulation of several genes induced by TSH [ 14 , 15 , 35 ], raised the question whether GLIS3 activity itself is controlled by TSH signaling. This hypothesis is supported by data showing that GLIS3 protein is greatly induced in thyroid follicular cells of mice fed a LID and that the level of GLIS3 protein and its transcriptional activity is significantly enhanced in PCCl3 cells by TSH, cAMP or the expression of constitutively active PKA.…”