title: PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations.
abstract: The mechanism of insulin gene transcription control in response to glucose concentration is poorly defined. The islet-restricted transcription factors PDX1 and ISL1 interact with BETA2, activating insulin gene expression. However, their contribution and hierarchical organization in insulin expression control based on glucose concentration remain unknown. We investigated PDX1 and ISL1 regulation of insulin gene expression in pancreatic β cells cultured in normal (5 mM/L) and high (25 mM/L) glucose conditions. ISL1 interacted with BETA2 to maintain basic insulin gene transcriptional activity under normal glucose. The ISL1-recruited cofactors SET9 and JMJD3 facilitated insulin gene histone modifications under normal glucose. In high-glucose concentrations, PDX1 formed a complex with BETA2 to enhance insulin gene expression. PDX1 also recruited SET9 and JMJD3 to promote the activation of histone modulation on the insulin promoter. This is the first evidence transcription factors orchestrate epigenetic modifications to control insulin gene expression based on glucose concentration.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China. Electronic address: chunyanzhou@bjmu.edu.cn.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D020690:GTPase-Activating Proteins; D005947:Glucose; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D018398:Homeodomain Proteins; D007328:Insulin; D056484:Jumonji Domain-Containing Histone Demethylases; D060850:LIM-Homeodomain Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C501008:Neurod1 protein, mouse; C490620:Ralbp1 protein, mouse; C063843:insulin gene enhancer binding protein Isl-1; C084010:pancreatic and duodenal homeobox 1 protein
keywords: Glucose; ISL1; Insulin; JMJD3; PDX1; SET9