Jazf1 acts as a regulator of insulin‐producing β‐cell differentiation in induced pluripotent stem cells and glucose homeostasis in mice

Abstract

Genetic susceptibility of type 2 diabetes and Juxtaposed with another zinc finger protein 1 (Jazf1) has been reported; however, the precise role of Jazf1 in metabolic processes remains elusive. In this study, using Jazf1knockout (KO)-induced pluripotent stem cells (iPSC), pancreatic beta cell line MIN6 cells, and Jazf-1 heterozygous KO (Jazf1 +/À ) mice, the effect of Jazf1 on gradual differentiation was investigated. We checked the alterations of the genes related with b-cell specification, maturation, and insulin release against glucose treatment by the gain and loss of the Jazf1 gene in the MIN6 cells. Because undifferentiated Jazf1-KO iPSC were not significantly different from wild-type (WT) iPSC, the size and endoderm marker expression after embryoid body (EB) and teratoma formation were investigated. Compared to EB and teratomas formed with WT iPSC, the EB and teratomas from with Jazf1-KO iPSC were smaller, and in teratomas, the expression of proliferation markers was reduced. Moreover, the expression of the gene sets for b-cell differentiation and the levels of insulin and C-peptide secreted by insulin precursor cells were notably reduced in b-cells differentiated from Jazf1-KO iPSC compared with those differentiated from WT iPSC. A comparison of Jazf1 +/À and WT mice showed that Jazf1 +/À mice had lower levels of serum insulin, pancreatic insulin expression, and decreased pancreatic b-cell size, which resulted in defects in the glucose homeostasis. These findings suggest that Jazf1 plays a pivotal role in the differentiation of b-cells and glucose homeostasis.Abbreviations Jazf1, Juxtaposed with another zinc finger protein 1; KO, knockout; iPSC, induced pluripotent stem cells; WT, wild-type; EB, embryoid body; Jazf1 +/À , Jazf1 heterozygous knockout; TR4, testicular nuclear receptor 4; MEF, mouse embryonic fibroblast.

Deletion of Jazf1 gene causes early growth retardation and insulin resistance in mice

“…Tr4 KO mice showed low IGF-1 serum concentrations and early growth retardation ( 27 ), similar to what we observed in Jazf1 KO mice. A recent study showed decreased GSIS in beta cell-specific Jazf1 KO mice under hyperglycemic condition ( 16 ) and in beta cells differentiated from Jazf1 KO ( 17 ). Thus, we tested whether TR4 expression or insulin secretion was affected in our animals.…”

“…A recent study generated a pancreatic β cell-specific Jazf1 knockout (KO) mouse, which had no discernible phenotype under basal conditions and decreases in glucose-stimulated insulin secretion (GSIS) under hyperglycemic challenged conditions ( 16 ). In contrast, others reported that mice heterozygous for a loss of function mutation had impaired insulin secretion ( 17 ). Although these studies suggest an association between JAZF1 and T2D, the causal relationship between JAZF1 and both T2D and height is still debated.…”

JAZF1: A metabolic actor subunit of the NuA4/TIP60 chromatin modifying complex

“…Consequently, JAZF1 overexpressing animals are protected against diet-induced insulin resistance and related metabolic dysfunctions (Jang et al, 2014;Li et al, 2014;Yuan et al, 2015;Wei et al, 2018;Zhou et al, 2020). Furthermore, JAZF1 has been linked to other equally important, metabolically relevant processes, including pancreatic beta cell differentiation and function (Taneera et al, 2012;Kobiita et al, 2020;Park et al, 2021), ribosome biogenesis (Kobiita et al, 2020;Procida et al, 2021) and adipogenesis (Ming et al, 2014a;Jeong et al, 2021).…”

Rs864745 in JAZF1, an Islet Function Associated Variant, Correlates With Plasma Lipid Levels in Both Type 1 and Type 2 Diabetes Status, but Not Healthy Subjects

“…Furthermore, JAZF1 is expressed in both human (3,4) and mouse b-cells (5,6). JAZF1 is an important regulator of endoplasmic reticulum (ER) stress and ribosome biogenesis via a feedback action preventing the activation of ER and p53 stress-mediated b-cell apoptosis (7), which plays a pivotal role in the differentiation of b-cells and glucose homeostasis (8). Obesity (9) and diabetes status (10,11) alter the JAZF1 expression pattern.…”