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YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic β-Cells
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 β-cells after birth. Never...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044128/ https://www.ncbi.nlm.nih.gov/pubmed/35113157 http://dx.doi.org/10.2337/db21-0695 |
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author | Liu, Di Yang, Kevin Y. Chan, Vicken W. Ye, Wenchu Chong, Charing C.N. Wang, Chi Chiu Wang, Huating Zhou, Bin Cheng, Kenneth K.Y. Lui, Kathy O. |
author_facet | Liu, Di Yang, Kevin Y. Chan, Vicken W. Ye, Wenchu Chong, Charing C.N. Wang, Chi Chiu Wang, Huating Zhou, Bin Cheng, Kenneth K.Y. Lui, Kathy O. |
author_sort | Liu, Di |
collection | PubMed |
description | 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 β-cells after birth. Nevertheless, the physiological role of YY1 during β-cell development and its regulatory mechanism in β-cell function remain largely unknown. After β-cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance, and reduced β-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 β-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 β-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 β-cell maturation and function after birth. These analyses may advance our understanding of β-cell biology and provide clinically relevant insights targeting the pathophysiological origins of diabetes. |
format | Online Article Text |
id | pubmed-9044128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-90441282022-05-11 YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic β-Cells Liu, Di Yang, Kevin Y. Chan, Vicken W. Ye, Wenchu Chong, Charing C.N. Wang, Chi Chiu Wang, Huating Zhou, Bin Cheng, Kenneth K.Y. Lui, Kathy O. Diabetes Islet Studies 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 β-cells after birth. Nevertheless, the physiological role of YY1 during β-cell development and its regulatory mechanism in β-cell function remain largely unknown. After β-cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance, and reduced β-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 β-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 β-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 β-cell maturation and function after birth. These analyses may advance our understanding of β-cell biology and provide clinically relevant insights targeting the pathophysiological origins of diabetes. American Diabetes Association 2022-05 2022-02-03 /pmc/articles/PMC9044128/ /pubmed/35113157 http://dx.doi.org/10.2337/db21-0695 Text en © 2022 by the American Diabetes Association https://www.diabetesjournals.org/journals/pages/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://diabetesjournals.org/journals/pages/license. |
spellingShingle | Islet Studies Liu, Di Yang, Kevin Y. Chan, Vicken W. Ye, Wenchu Chong, Charing C.N. Wang, Chi Chiu Wang, Huating Zhou, Bin Cheng, Kenneth K.Y. Lui, Kathy O. YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic β-Cells |
title | YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic β-Cells |
title_full | YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic β-Cells |
title_fullStr | YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic β-Cells |
title_full_unstemmed | YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic β-Cells |
title_short | YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic β-Cells |
title_sort | yy1 regulates glucose homeostasis through controlling insulin transcription in pancreatic β-cells |
topic | Islet Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044128/ https://www.ncbi.nlm.nih.gov/pubmed/35113157 http://dx.doi.org/10.2337/db21-0695 |
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