YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic Beta Cells

To date, identification of non-islet specific transcriptional factors in the regulation of insulin gene expression has been less studied. Here, we report that the expression level of the transcription factor YY1 has increased dramatically after birth in both human and mouse pancreatic beta cells. Nevertheless, the physiological role of YY1 during beta cell development, and its regulatory mechanism in beta cell function remain largely unknown. Following beta cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance and reduced beta cell mass in both neonates and adult mice. These mice also displayed hypoinsulinemia with normal insulin sensitivity compared to their wildtype littermates, manifesting as a type-1 diabetic phenotype. Mechanistically, genome-wide RNA-seq has defined dysregulated insulin signalling and defective glucose responsiveness in beta cells devoid of YY1. Integrative analyses coupled with chromatin immunoprecipitation (ChIP) assays targeting YY1 and histone modifications including H3K4me1, H3K27ac and H3K27me3 have further identified Ins1 and Ins2 as direct gene targets of YY1. Further analyses through luciferase reporter assays, loss- and gain-of-function experiments demonstrate 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 stabilising the enhancer-promoter interaction in the multiprotein-DNA complex during transcription initiation. Taken together, our findings have suggested a hitherto novel role of YY1 as a transcriptional activator of insulin gene expression, assisting beta cell maturation and function after birth. These studies may advance our understanding of beta cell biology with clinically relevant insights targeting the pathophysiological origins of diabetes.