Mechanism Of Action And Functions Of The Gli-related Proteins Glis 1-3

National Institute Of Environmental Health Sciences

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Abstract

Glis1-3 are novel genes identified in our laboratory. The Glis1-3 genes encode Kruppel-like zinc finger proteins containing five tandem zinc finger motifs that exhibit highest homology with those of members of the Gli and Zic subfamilies of Kruppel-like zinc finger proteins. Glis3: Glis3 plays a critical role in pancreatic development and has been implicated in a syndrome with neonatal diabetes and hypothyroidism (NDH). Glis3 is highly expressed in pancreatic beta cells where it regulates the transcription of several beta cell genes, including the insulin gene, by binding to Glis-binding sites in their promoter region. Glis3 regulates the transcription of these genes in coordination with other beta cell transcription factors. During pancreatic development Glis3 is expressed as early as in the bipotent pancreatic progenitors and remains expressed in pancreatic ducts and endocrine progenitors and pancreatic beta cells. Glis3 deficiency leads to the development of neonatal diabetes, due to reduced insulin gene expression and in the number of pancreatic beta cells. Glis3 plays a critical role in the transcriptional regulation of insulin in pancreatic beta cells by recruiting CBP/p300, which may serve as a scaffold for the formation of a larger transcriptional regulatory complex containing Pdx1, NeuroD1, and MafA at the insulin promoter. Single cell RNA sequencing (scRNA-Seq) of embryonic pancreas have revealed new insights into the role of Glis3 in pancreatic beta cells generation and maturation. Dysfunction of Glis3 also leads to development of cystic renal disease suggesting that Glis3 plays a critical role in maintaining normal renal functions. Glis3 was shown to promote metabolic reprogramming in early postnatal kidney and regulate mitochondrial functions. RIME mass spectrometry identified several Glis3-interacting proteins and post-translational modifications. Glis3 further plays a critical role in spermatogenesis. It is expressed in spermatogonial stem cells and becomes down-regulated when these cells differentiate into differentiated spermatogonia. Mice deficient in Glis3 are deficient in mature spermatozoa and therefore infertile. Glis3 is also critical in the synthesis of thyroid hormone in that Glis3 deficiency results in hypothyroidism due to a greatly reduced thyroid hormone production. Glis3 is essential for thyroid hormone biosynthesis and thyroid follicular cell proliferation. Under iodide-deficiency conditions Glis3 knockout mice do not develop goiter in contrast to wild type mice. Glis3 regulates thyroid gene expression in coordination with other thyroid transcription factors. GLIS3 is highly expressed in osteoblasts, astrocytes, and ependymal cells where it regulates the expression of specific genes and cell functions. Glis2 is highly expressed in kidney. To obtain insight into the physiological functions of Glis2, mice deficient in Glis2 were generated. Glis2 deficient mice develop a chronic kidney disease, nephronophthisis, that is accompanied by renal atrophy, fibrosis and inflammation. Ultimately Glis2 deficient mice die prematurely of renal failure. A large number of genes involved in immune responses/inflammation and fibrosis/tissue remodeling are induced in kidneys of Glis2 deficient mice. results in renal failure. Our study indicates that Glis2 plays a critical role in the regulation of renal inflammation and the maintenance of normal kidney functions. Glis2 represses the transcription of several inflammatory genes. GLIS2 is overexpressed in breast cancer where it plays a role in regulating epithelial transition. Glis1 knockout mice develop proptosis that is related to increased intraocular pressure (IOP) characteristic of glaucoma. The increase in IOP is related to degeneration of the trabecular meshwork, a tissue that is important in draining fluid from the anterior chamber. ChIP-Seq analysis identified a number of genes that are directly regulated by GLIS1 in the trabecular meshwork. GWAS studies found and association between a single nucleotide polymorphism in GLIS1 and increased of glaucoma.