Chromatin Cofactors in Islet Development and Function

胰岛发育和功能中的染色质辅助因子

• 批准号: 8443853
• 负责人: Raghavendra G Mirmira
• 金额: $ 27.4万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443853
• 关键词: Address; Adult; Affect; American; Animals; Biochemical; Biological Assay; Cell physiology; Cells; Chromatin; Chromatin Structure; Complement; Complex; Data; Diabetes Mellitus; Disease; Euchromatin; Exhibits; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Glucose Intolerance; Goals; Grant; Growth; Heterochromatin; Histone H3; Histones; In Vitro; Incidence; Individual; Insulin; Islet Cell; Laboratories; Maintenance; Mediating; Modification; Morphogenesis; Mus; Nucleic Acid Regulatory Sequences; Pancreas; Phenocopy; Primordium; Reporter Genes; Research; Role; Signal Pathway; Testing; Transcriptional Activation; Transgenic Mice; bZIP Domain; blood glucose regulation; cell type; chromatin modification; cofactor; endocrine pancreas development; gain of function; histone modification; in vivo; insight; islet; pancreas development; public health relevance; research study; transcription factor

DESCRIPTION (provided by applicant): The overall objective of my laboratory is to define the biochemical mechanisms underlying gene regulation in the developing and mature islet 2 cell. In recent years, a greater emphasis has been placed on the role of covalent histone modifications in mammalian gene transcription, particularly how such modifications enable states of open or closed chromatin (euchromatin or heterochromatin, respectively) at specific genetic loci. The collective studies of several laboratories including our own have established that Pdx1, a master transcriptional regulator in the pancreas, controls gene expression in part through recruitment of cofactors that covalently modify histones. Dimethylated histone H3-Lys4 appears to be a crucial euchromatin marker in differentiating and mature islets. Therefore, in principle, many of the effects of Pdx1 on pancreas development and islet function could be explained by its recruitment of histone methylating cofactors. We have identified a remarkably islet-enriched cofactor, Set7/9, that appears to be responsible for dimethylated H3-Lys4 at many Pdx1 target genes. Our preliminary studies show that Set7/9 haploinsufficiency in the islet leads to impaired transcription of many Pdx1 targets and causes islet dysfunction and glucose intolerance, effectively phenocopying Pdx1 haploinsufficiency itself. Thus, the overarching hypothesis of this proposal is that Set7/9 is a chromatin-modifying cofactor that functions as an effector of Pdx1 action in the developing and mature islet. To test this hypothesis, we propose the following 3 specific aims: Aim 1: Determine the role of Set7/9 in directing islet cell fate and mass accrual during pancreas development. Aim 2: Determine the role of Set7/9 in the maintenance of normal islet function and glucose homeostasis. Aim 3: Determine how a transcriptional complex involving Set7/9 and Pdx1 regulates MafA gene transcription in the developing and mature 2 cell. We believe that the successful completion of these aims will identify both the role and mechanisms of a crucial chromatin-modifying cofactor in islet development and function.

描述(申请人提供)：我的实验室的总体目标是确定在发育和成熟的胰岛2细胞中潜在的基因调控的生化机制。近年来，共价组蛋白修饰在哺乳动物基因转录中的作用受到越来越多的重视，特别是这种修饰如何使特定遗传位点上的染色质处于开放或闭合状态(分别为常染色质或异染色质)。包括我们自己在内的几个实验室的集体研究已经证实，Pdx1是胰腺中的主要转录调节因子，部分通过招募共价修饰组蛋白的辅助因子来控制基因表达。二甲基化组蛋白H3-Lys4似乎是分化和成熟胰岛的关键常染色质标记物。因此，原则上，Pdx1对胰腺发育和胰岛功能的许多影响可以通过其组蛋白甲基化辅助因子的募集来解释。我们已经确定了一个显著丰富的胰岛辅助因子Set7/9，它似乎是许多Pdx1靶基因上H3-Lys4甲基化的原因。我们的初步研究表明，胰岛Set7/9单倍体不足导致许多Pdx1靶标转录受损，导致胰岛功能障碍和糖耐量异常，有效地复制了Pdx1单倍体不足本身。因此，这一建议的主要假设是，Set7/9是染色质修饰的辅助因子，在发育和成熟的胰岛中发挥Pdx1作用的效应器的作用。为了验证这一假设，我们提出了以下三个具体目标：目标1：确定Set7/9在指导胰岛细胞命运和胰腺发育过程中质量积累中的作用。目的2：探讨Set7/9在维持正常胰岛功能和维持血糖稳态中的作用。目的3：确定Set7/9和Pdx1的转录复合体如何在发育和成熟的2细胞中调节MafA基因的转录。我们相信，这些目标的成功完成将确定一个关键的染色质修饰辅助因子在胰岛发育和功能中的作用和机制。