TY - JOUR
T1 - YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic b-Cells
AU - Liu, Di
AU - Yang, Kevin Y.
AU - Chan, Vicken W.
AU - Ye, Wenchu
AU - Chong, Charing C.N.
AU - Wang, Chi Chiu
AU - Wang, Huating
AU - Zhou, Bin
AU - Cheng, Kenneth K.Y.
AU - Lui, Kathy O.
N1 - Funding Information:
Acknowledgments. We thank Prof. Douglas A. Melton (Harvard University) for the gift of Pdx1CreER. Funding. This work was supported by the National Natural Science Foundation of China (grants 81922077 and 82070494), Research Grants Council of Hong Kong (grants 14100021, 14108420, C4026-17WF, and M-402-20), Croucher Foundation (Innovation Award), University Grants Committee Research Matching Grant Scheme (2019, 2020, and 2021), Research Committee Funding, Direct Grants, Faculty Innovation Award, Young Researcher Award, and postdoctoral fellowships (K.Y.Y., W.Y.) and a postgraduate studentship (D.L.) from the Chinese University of Hong Kong. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. D.L., K.Y.Y., V.W.C., and W.Y. performed experiments and analyzed the data; D.L., K.K.Y.C. and K.O.L. interpreted the data; C.C.N.C. and C.C.W. recruited human volunteers and provided clinical samples; H.W. and B.Z. provided reagents; and K.O.L. designed experiments, supervised the research, and wrote the manuscript. K.O.L. also is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2022 by the American Diabetes Association.
PY - 2022/5
Y1 - 2022/5
N2 - 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 b-cells after birth. Nevertheless, the physiological role of YY1 during b-cell development and its regulatory mechanism in b-cell function remain largely unknown. After b-cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance, and reduced b-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 b-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 b-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 b-cell maturation and function after birth. These analyses may advance our understanding of b-cell biology and provide clinically relevant insights targeting the pathophysiological origins of diabetes.
AB - 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 b-cells after birth. Nevertheless, the physiological role of YY1 during b-cell development and its regulatory mechanism in b-cell function remain largely unknown. After b-cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance, and reduced b-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 b-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 b-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 b-cell maturation and function after birth. These analyses may advance our understanding of b-cell biology and provide clinically relevant insights targeting the pathophysiological origins of diabetes.
UR - http://www.scopus.com/inward/record.url?scp=85128800783&partnerID=8YFLogxK
U2 - 10.2337/db21-0695
DO - 10.2337/db21-0695
M3 - Journal article
C2 - 35113157
AN - SCOPUS:85128800783
SN - 0012-1797
VL - 71
SP - 961
EP - 977
JO - Diabetes
JF - Diabetes
IS - 5
ER -