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

Abstract

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.

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

“…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.…”

“…GLI Similar 3 (GLIS3), a Krüppel-like zinc finger transcription factor, plays a critical role in the regulation of many biological processes, including pancreatic β-cell generation, spermatogenesis, and thyroid hormone biosynthesis [25][26][27][28][29][30][31]. Recently, GLIS3 was shown to effectively promote reprogramming of somatic cells into embryonic stem cells (ESCs) [32,33].…”

GLIS3 and Thyroid: A Pleiotropic Candidate Gene for Congenital Hypothyroidism

“…Furthermore, GLIS3 stability is regulated by the binding with the “Suppressor of Fused” (SUFU), a negative regulator of Hedgehog (SHH) signaling, via a YGH motif localized into the N-terminal domain ( 7 ). SUFU not only protects Glis3 from proteasomal degradation stabilizing Glis3 protein ( 8 ), but also modulates Glis3-mediated transactivation of the promoter of target genes ( 9 ).…”

“…The GLIS3 alterations identified in NDH patients included missense substitutions, frameshift mutations resulting in premature termination, deletions encompassing exons 5–9, 3–4, 9–11, 10–11 and larger deletions covering regions >100 kb that include exons 1–2, 1–4, or 5–9 ( 8 ).…”

Oncogenic properties and signaling basis of the PAX8‐GLIS3 fusion gene

“…PAX8 is a member of the paired box family of transcription factors involved in embryogenesis and cellular differentiation playing an important role in thyroid development and thyroid‐specific gene expression 6,7 . GLIS3 is a Kruppel‐like zinc finger transcription factor that participates in proliferation, apoptosis, cellular differentiation and embryological development, 8,9 and is expressed in thyroid follicular cells under physiologic conditions 10 . Deficiency in GLIS3 is associated with congenital hypothyroidism 8,10 .…”