Chromatin Cofactors in Islet Development and Function

胰岛发育和功能中的染色质辅助因子

基本信息

批准号：
8245180
负责人：
Raghavendra G Mirmira
金额：
$ 28.71万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245180
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Diabetes is a disorder of insulin-producing and insulin-responsive cells that afflicts 24 million Americans, and its incidence is rising at an alarming rate. The specific goal of this grant is to investigate how genes are regulated in insulin-producing cells. Overall, this project seeks to understand how insulin-producing cells are formed and how specific genes might be used to reprogram other cell types to become insulin-producing cells for individuals with diabetes.

描述（由申请人提供）：我实验室的总体目的是定义发育和成熟胰岛2细胞中基因调节基因调节的生化机制。近年来，已经更加重视了共价组蛋白在哺乳动物基因转录中的作用，尤其是这种修饰如何使特定遗传基因座的开放或封闭染色质或闭合染色质（euchromatin或异染色质分别）的状态如何实现。对包括我们自己在内的几个实验室的集体研究已经确定，胰腺中的主要转录调节剂PDX1通过募集共价修改组蛋白的辅助因子来部分控制基因表达。二甲基化的组蛋白H3-LYS4似乎是分化和成熟胰岛中至关重要的白素标记。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募集组蛋白甲基化辅因子来解释。我们已经确定了一个非常富含胰岛的辅因子Set7/9，在许多PDX1靶基因下似乎负责二甲基化的H3-LYS4。我们的初步研究表明，胰岛中的SET7/9单倍不足会导致许多PDX1靶标和原因胰岛功能障碍和葡萄糖不耐受的转录受损，从而有效地表现了PDX1单倍耐药物本身。因此，该提案的总体假设是set7/9是一种染色质修饰的辅助因子，在发育和成熟胰岛中起作用PDX1作用的效应因子。为了检验这一假设，我们提出以下3个特定目标：目标1：确定set7/9在胰腺发育过程中指导胰岛命运和质量应计的作用。目标2：确定SET7/9在维持正常胰岛功能和葡萄糖稳态中的作用。 AIM 3：确定涉及Set7/9和PDX1的转录复合物如何调节发育和成熟2细胞中的MAFA基因转录。我们认为，这些目标的成功完成将确定胰岛发育和功能中关键染色质调节辅助因子的作用和机制。公共卫生相关性：糖尿病是一种产生胰岛素和胰岛素反应性细胞的疾病，遭受了2400万美国人的疾病，其发病率正在以惊人的速度上升。该赠款的具体目标是研究如何在产生胰岛素的细胞中调节基因。总体而言，该项目试图了解如何形成产生胰岛素的细胞，以及如何使用特定基因重新编程其他细胞类型，以成为糖尿病患者产生胰岛素的细胞。