| First Author | Liu D | Year | 2022 |
| Journal | Diabetes | Volume | 71 |
| Issue | 5 | Pages | 961-977 |
| PubMed ID | 35113157 | Mgi Jnum | J:324240 |
| Mgi Id | MGI:7266557 | Doi | 10.2337/db21-0695 |
| Citation | Liu D, et al. (2022) YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic beta-Cells. Diabetes 71(5):961-977 |
| abstractText | To date, identification of nonislet-specific transcriptional factors in the regulation of insulin gene expression has been little studied. Here, we report that the expression level of the transcription factor YY1 is increased dramatically in both human and mouse pancreatic beta-cells after birth. Nevertheless, the physiological role of YY1 during beta-cell development and its regulatory mechanism in beta-cell function remain largely unknown. After beta-cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance, and reduced beta-cell mass in neonatal and adult mice. These mice also had hypoinsulinemia with normal insulin sensitivity compared with their wild-type littermates, manifesting as a type 1 diabetic phenotype. Mechanistically, genome-wide RNA sequencing has defined dysregulated insulin signaling and defective glucose responsiveness in beta-cells devoid of YY1. Integrative analyses coupled with chromatin immunoprecipitation assays targeting YY1, and histone modifications, including H3K4me1, H3K27ac, and H3K27me3, have further identified Ins1 and Ins2 as direct gene targets of YY1. Luciferase reporter assays and loss- and gain-of-function experiments also demonstrated that YY1 binds to the enhancer regions in exon 2 of Ins1 and Ins2, activating insulin transcription and, therefore, proinsulin and insulin production in pancreatic beta-cells. YY1 also directly interacts with RNA polymerase II, potentially stabilizing the enhancer-promoter interaction in the multiprotein-DNA complex during transcription initiation. Taken together, our findings suggest a role for YY1 as a transcriptional activator of insulin gene expression, assisting beta-cell maturation and function after birth. These analyses may advance our understanding of beta-cell biology and provide clinically relevant insights targeting the pathophysiological origins of diabetes. |
