Transcriptional Regulation of Hepatocyte Differentiation and Function

肝细胞分化和功能的转录调控

• 批准号: 8486428
• 负责人: Lisa A Cirillo
• 金额: $ 32.11万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486428
• 关键词: Acetylation; Address; Adult; Alleles; Bile Acids; Binding; Biological; Cells; Cholesterol; Cholesterol Homeostasis; Chromatin; Chromatin Structure; Congenital Abnormality; DNA; DNA Binding Domain; DNA Polymerase II; Data; Development; Diabetes Mellitus; Disease; Embryo; Environment; Event; Failure; Fatty Liver; Fibrosis; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Glucose; Goals; Hepatic; Hepatocyte; Hip region structure; Histones; Hormonal; Human; In Vitro; Intervention; Link; Liver; Liver Fibrosis; Liver diseases; Maintenance; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mus; Mutation; Neoplasms; Nucleoproteins; Nucleosomes; Organism; Patients; Phosphorylation; Physiological; Post-Translational Protein Processing; Proteins; RNA; RNA Polymerase II; Recruitment Activity; Regulation; Regulator Genes; Role; Signal Pathway; Signal Transduction; Stimulus; Structure; System; Techniques; Testing; Tissue Differentiation; Tissues; Transcriptional Regulation; Work; base; cell type; chromatin modification; chromatin remodeling; genetic regulatory protein; hormone regulation; induced pluripotent stem cell; knock-down; lipid metabolism; mutant; novel; preempt; prevent; programs; research study; response; stem; transcription factor

DESCRIPTION (provided by applicant): A critical, unresolved issue in gene regulation is the means by which chromatin that packages developmentally regulated genes is accessed and remodeled to orchestrate cell-type specific gene expression programs informing tissue differentiation and function. This poses a critical dilemma in cells of both the developing embryo, in which much of the chromatin is still compacted, and the adult organism, where alterations in gene expression in response to signaling cascades directing essential physiological functions necessitate rapid alterations in the chromatin landscape. Failure to properly navigate either of these biological challenges can have grave biomedical consequences in the form of congenital malformations, disease, and neoplasia in humans. Based on the ability of the initial "pioneer" chromatin binding transcription factor FoxO1 to remodel histone:DNA contacts within compacted chromatin in vitro, its recruitment of liver-enriched regulatory factors and RNA pol II to regulatory targets in hepatocytes, and regulation of these activities by posttranslational modifications linked to signaling pathways with proven roles in maintenance of glucose, bile acid and cholesterol homeostasis in humans we hypothesize that FoxO1 cooperates with closely juxtaposed liver- enriched transcription factors to carry out chromatin structural alterations necessary for developmental activation of hepatic genes crucial to human hepatocyte function. We argue that posttranslational modification of the FoxO1 DNA binding domain enables hormonal regulation of FoxO1 target genes in the human liver by disrupting this relationship. This proposal addresses two key questions that stem from this hypothesis: 1) How does FoxO1 cooperate with other liver-enriched regulatory factors to carry out chromatin remodeling and modification necessary for developmental activation of hepatic genes? and 2) Is this cooperation necessary for hormonal regulation of transcriptionally active chromatin encoding essential metabolic functions in the human liver? To accomplish this goal, we will use a novel hiPS (human induced pluripotent stem) cell human hepatocyte differentiation system to uncover basic molecular mechanisms informing the function and regulation of FoxO1 under conditions that recapitulate hepatocyte specification, differentiation, and function in humans. We will also use state of the art molecular techniques that enable the assembly and analysis of defined nucleoprotein structures to test mechanisms implicated by our observations. FoxO1 is now established as a key transcriptional regulator integrating hepatic glucose, cholesterol, bile acid, and lipid metabolism in humans; mutant FoxO1 alleles are recently demonstrated in diabetes and hepatic steatosis and fibrosis in human patients. Our hypothesis assumes that the chromatin binding and remodeling capabilities attributed to FoxO1 are essential for the assembly of the nucleoprotein structures tasked with activating FoxO1 target genes and mediating their response to diverse signaling cascades. Subversion of these gene regulatory events is a likely contributor to metabolic derangements and hepatic disease, making it vital that we uncover the key mechanisms and players.

描述（由申请人提供）：基因调控中一个关键的、未解决的问题是染色质如何被访问和重塑，以协调细胞类型特定的基因表达程序，从而通知组织分化和功能。这给正在发育的胚胎细胞、