PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations. (15th June 2016)

• Record Type: Journal Article
• Authors: Wang, Weiping; Shi, Qiong; Guo, Ting; Yang, Zhe; Jia, Zhuqing; Chen, Ping; Zhou, Chunyan
• Is Part Of: Molecular and cellular endocrinology. Volume 428(2016)
• Page Start: 38
• Page End: 48
• Publication Date: 2016-06-15
• Subjects: Insulin -- PDX1 -- ISL1 -- Glucose -- SET9 -- JMJD3; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2016.03.019
• Languages: English
• ISSNs: 0303-7207

Abstract

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. Highlights: We propose a novel insulin gene regulation pattern responding to glucose signaling. ISL1–BETA2 complex maintains basic insulin gene expression under normal glucose. PDX1–BETA2 complex enhances insulin gene expression in high-glucose conditions. SET9 and JMJD3 aid INS gene histone modification in different glucose conditions.